Passivation, pH protective or lubricity coating for pharmaceutical package, coating process and apparatus

ABSTRACT

A method for providing a passivation layer or pH protective coating on a substrate surface by PECVD is provided, the method comprising generating a plasma from a gaseous reactant comprising polymerizing gases. The lubricity, passivation, pH protective, hydrophobicity, and/or barrier properties of the passivation layer or pH protective coating are set by setting the ratio of the O2 to the organosilicon precursor in the precursor feed, and/or by setting the electric power used for generating the plasma. In particular, a passivation layer or pH protective coating made by the method is provided. Pharmaceutical packages coated by the method and the use of such packages protecting composition contained in the vessel against mechanical and/or chemical effects of the surface of the package without a passivation layer or pH protective coating material are also provided.

This application is a divisional of U.S. Ser. No. 14/357,418, which is aU.S. National Phase Application of International Application No.PCT/US2012/064489, filed Nov. 9, 2012, which claims priority from U.S.Provisional Application Ser. No. 61/558,885, filed Nov. 11, 2011;61/636,377, filed Apr. 20, 2012; and U.S. Ser. No. 61/645,003, filed May9, 2012. All of these applications are incorporated here by reference intheir entirety

U.S. Provisional Ser. Nos. 61/177,984 filed May 13, 2009; 61/222,727,filed Jul. 2, 2009; 61/213,904, filed Jul. 24, 2009; 61/234,505, filedAug. 17, 2009; 61/261,321, filed Nov. 14, 2009; 61/263,289, filed Nov.20, 2009; 61/285,813, filed Dec. 11, 2009; 61/298,159, filed Jan. 25,2010; 61/299,888, filed Jan. 29, 2010; 61/318,197, filed Mar. 26, 2010;61/333,625, filed May 11, 2010; 61/413,334, filed Nov. 12, 2010; Ser.No. 12/779,007, filed May 12, 2010, now U.S. Pat. No. 7,985,188;International Application PCT/US11/36097, filed May 11, 2011; U.S. Ser.No. 61/558,885, filed Nov. 11, 2011; U.S. Ser. No. 61/636,377, filedApr. 20, 2012; U.S. Ser. No. 61/645,003, filed May 9, 2012; and U.S.Ser. No. 61/716,381, filed Oct. 19, 2012; are all incorporated here byreference in their entirety.

Also incorporated by reference in their entirety are the followingEuropean patent applications: EP10162755.2 filed May 12, 2010;EP10162760.2 filed May 12, 2010; EP10162756.0 filed May 12, 2010;EP10162758.6 filed May 12, 2010; EP10162761.0 filed May 12, 2010; andEP10162757.8 filed May 12, 2010.

FIELD OF THE INVENTION

The present invention relates to the technical field of coated surfaces,for example interior surfaces of pharmaceutical packages or othervessels for storing or other contact with fluids. Examples of suitablefluids include foods or biologically active compounds or body fluids,for example blood. The present invention also relates to apharmaceutical package or other vessel and to a method for coating aninner or interior surface of a pharmaceutical package or other vessel.The present invention also relates more generally to medical devices,including devices other than packages or vessels, for example catheters.

The present disclosure also relates to improved methods for processingpharmaceutical packages or other vessels, for example multiple identicalpharmaceutical packages or other vessels used for pharmaceuticalpreparation storage and delivery, venipuncture and other medical samplecollection, and other purposes. Such pharmaceutical packages or othervessels are used in large numbers for these purposes, and must berelatively economical to manufacture and yet highly reliable in storageand use.

BACKGROUND OF THE INVENTION

One important consideration in manufacturing pharmaceutical packages orother vessels for storing or other contact with fluids, for examplevials and pre-filled syringes, is that the contents of thepharmaceutical package or other vessel desirably will have a substantialshelf life. During this shelf life, it can be important to isolate thematerial filling the pharmaceutical package or other vessel from thevessel wall containing it, or from barrier coatings or layers or otherfunctional layers applied to the pharmaceutical package or other vesselwall to avoid leaching material from the pharmaceutical package or othervessel wall, barrier coating or layer, or other functional layers intothe prefilled contents or vice versa.

Since many of these pharmaceutical packages or other vessels areinexpensive and used in large quantities, for certain applications itwill be useful to reliably obtain the necessary shelf life withoutincreasing the manufacturing cost to a prohibitive level.

For decades, most parenteral therapeutics have been delivered to endusers in Type I medical grade borosilicate glass vessels such as vialsor pre-filled syringes. The relatively strong, impermeable and inertsurface of borosilicate glass has performed adequately for most drugproducts. However, the recent advent of costly, complex and sensitivebiologics as well as such advanced delivery systems as auto injectorshas exposed the physical and chemical shortcomings of glasspharmaceutical packages or other vessels, including possiblecontamination from metals, flaking, delamination, and breakage, amongother problems. Moreover, glass contains several components which canleach out during storage and cause damage to the stored material.

In more detail, borosilicate pharmaceutical packages or other vesselsexhibit a number of drawbacks.

Glass is manufactured from sand containing a heterogeneous mixture ofmany elements (silicon, oxygen, boron, aluminum, sodium, calcium) withtrace levels of other alkali and earth metals. Type I borosilicate glassconsists of approximately 76% SiO₂, 10.5% B₂O₃, 5% Al₂O₃, 7% Na₂O and1.5% CaO and often contains trace metals such as iron, magnesium, zinc,copper and others. The heterogeneous nature of borosilicate glasscreates a non-uniform surface chemistry at the molecular level. Glassforming processes used to create glass vessels expose some portions ofthe vessels to temperatures as great as 1200° C. Under such hightemperatures alkali ions migrate to the local surface and form oxides.The presence of ions extracted from borosilicate glass devices may beinvolved in degradation, aggregation and denaturation of some biologics.Many proteins and other biologics must be lyophilized (freeze dried),because they are not sufficiently stable in solution in glass vials orsyringes.

In glass syringes, silicone oil is typically used as a lubricant toallow the plunger tip, piston, stopper, or seal to slide in the barrel.Silicone oil has been implicated in the precipitation of proteinsolutions such as insulin and some other biologics. Additionally, thesilicone oil coating or layer is often non-uniform, resulting in syringefailures in the market.

Glass pharmaceutical packages or other vessels are prone to breakage ordegradation during manufacture, filling operations, shipping and use,which means that glass particulates may enter the drug. The presence ofglass particles has led to many FDA Warning Letters and to productrecalls.

Glass-forming processes do not yield the tight dimensional tolerancesrequired for some of the newer auto-injectors and delivery systems.

As a result, some companies have turned to plastic pharmaceuticalpackages or other vessels, which provide tighter dimensional tolerancesand less breakage than glass.

Although plastic is superior to glass with respect to breakage,dimensional tolerances and surface uniformity, its use for primarypharmaceutical packaging remains limited due to the followingshortcomings:

-   -   Gas (oxygen) permeability: Plastic allows small molecule gases        to permeate into (or out of) the device. The permeability of        plastics to gases can be significantly greater than that of        glass and, in many cases (as with oxygen-sensitive drugs such as        epinephrine), plastics previously have been unacceptable for        that reason.    -   Water vapor transmission: Plastics allow water vapor to pass        through devices to a greater degree than glass. This can be        detrimental to the shelf life of a solid (lyophilized) drug.        Alternatively, a liquid product may lose water in an arid        environment.    -   Leachables and extractables: Plastic pharmaceutical packages or        other vessels contain organic compounds that can leach out or be        extracted into the drug product. These compounds can contaminate        the drug and/or negatively impact the drug's stability.

Clearly, while plastic and glass pharmaceutical packages or othervessels each offer certain advantages in pharmaceutical primarypackaging, neither is optimal for all drugs, biologics or othertherapeutics. Thus, there can be a desire for plastic pharmaceuticalpackages or other vessels, in particular plastic syringes, with gas andsolute barrier properties which approach the properties of glass.Moreover, there can be a need for plastic syringes with sufficientlubricity and/or passivation or protective properties and a lubricityand/or passivation layer or pH protective coating which can becompatible with the syringe contents. There also can be a need for glassvessels with surfaces that do not tend to delaminate or dissolve orleach constituents when in contact with the vessel contents.

There are additional considerations to be taken into account whenmanufacturing a prefilled syringe. Prefilled syringes are commonlyprepared and sold so the syringe does not need to be filled before use,and can be disposed of after use. The syringe can be prefilled withsaline solution, a dye for injection, or a pharmaceutically activepreparation, for some examples.

Commonly, the prefilled syringe can be capped at the distal end, as witha cap (or, if the hypodermic needle is preinstalled, a needle shieldthat can also be a cap), and can be closed at the proximal end by itsdrawn plunger tip, piston, stopper, or seal. The prefilled syringe canbe wrapped in a sterile package before use. To use the prefilledsyringe, the packaging and cap are removed, optionally a hypodermicneedle or another delivery conduit can be attached to the distal end ofthe barrel, the delivery conduit or syringe can be moved to a useposition (such as by inserting the hypodermic needle into a patient'sblood vessel or into apparatus to be rinsed with the contents of thesyringe), and the plunger tip, piston, stopper, or seal can be advancedin the barrel to inject the contents of the barrel.

An important consideration regarding medical syringes can be to ensurethat the plunger tip, piston, stopper, or seal can move at a constantspeed and with a constant force when it is pressed into the barrel. Asimilar consideration applies to vessels such as pharmaceutical vialswhich have to be closed by a stopper, and to the stopper itself, andmore generally to any surface which is to provide smooth operation ofmoving parts and/or be passivated or protectively coated.

A non-exhaustive list of documents of possible relevance includes U.S.Pat. Nos. 7,901,783; 6,068,884; 4,844,986; and 8,067,070 and U.S. Publ.Appl. Nos. 2008/0090039, 2011/0152820, 2006/0046006 and 2004/0267194.These documents are all incorporated by reference.

SUMMARY OF THE INVENTION

An aspect of the invention is a filled package comprising a vessel, abarrier coating or layer, and a passivation layer or pH protectivecoating on the vessel, and a fluid composition contained in the vessel.The calculated shelf life of the package can be more than six months ata storage temperature of 4° C.

The vessel can have a lumen defined at least in part by a wall. The wallcan have an interior surface facing the lumen and an outer surface.

The barrier coating or layer comprises SiO_(x), wherein x is from 1.5 to2.9, from 2 to 1000 nm thick. The barrier coating or layer of SiO_(x)can have an interior surface facing the lumen and an outer surfacefacing the wall interior surface.

The passivation layer or pH protective coating comprises SiO_(x)C_(y) orSiN_(x)C_(y) wherein x is from about 0.5 to about 2.4 and y is fromabout 0.6 to about 3. Optionally in one embodiment, x can be about 1.1and y can be about 1.1. The passivation layer or pH protective coatingcan have an interior surface facing the lumen and an outer surfacefacing the interior surface of the barrier coating or layer. Thepassivation layer or pH protective coating can be effective to increasethe calculated shelf life of the package (total Si/Si dissolution rate).

The fluid composition can be contained in the lumen and can have a pHbetween 4 and 10, alternatively between 5 and 9.

Another aspect of the invention can be a filled package comprising avessel, a passivation layer or pH protective coating on the vessel, anda fluid composition contained in the vessel.

The vessel can have a lumen defined at least in part by a wall. The wallcan have an interior surface comprising glass facing the lumen and anouter surface.

The passivation layer or pH protective coating comprises SiO_(x)C_(y) orSiN_(x)C_(y) wherein x is from about 0.5 to about 2.4 and y is fromabout 0.6 to about 3. The passivation layer or pH protective coating canhave an interior surface facing the lumen and an outer surface facingthe interior surface of the barrier coating or layer. The passivationlayer or pH protective coating can be effective to decrease the Sidissolution rate of the glass interior surface.

The fluid composition can be contained in the lumen and can have a pHbetween 4 and 10, alternatively between 5 and 9.

Still another aspect of the invention can be an article comprising awall, a barrier coating or layer, and a passivation layer or pHprotective coating.

The wall can have an interior surface facing the lumen.

The barrier coating or layer comprises SiO_(x), wherein x is from 1.5 to2.9, from 2 to 1000 nm thick. The barrier coating or layer of SiO_(x)can have an interior surface facing the lumen and an outer surfacefacing the wall interior surface. The barrier coating or layer can beeffective to reduce the ingress of atmospheric gas through the wallcompared to an uncoated wall.

The passivation layer or pH protective coating can be on the barriercoating or layer, optionally with one or more intervening layers, andcomprises SiO_(x)C_(y) or SiN_(x)C_(y) wherein x is from about 0.5 toabout 2.4 and y is from about 0.6 to about 3. The passivation layer orpH protective coating can be formed by chemical vapor deposition of aprecursor selected from a linear siloxane, a monocyclic siloxane, apolycyclic siloxane, a polysilsesquioxane, a linear silazane, amonocyclic silazane, a polycyclic silazane, a polysilsesquiazane, asilatrane, a silquasilatrane, a silproatrane, an azasilatrane, anazasilquasiatrane, an azasilproatrane, or a combination of any two ormore of these precursors. The rate of erosion of the passivation layeror pH protective coating, if directly contacted by a fluid compositionhaving a pH between 4 and 10, alternatively between 5 and 9, can be lessthan the rate of erosion of the barrier coating or layer, if directlycontacted by the fluid composition.

Even another aspect of the invention can be a vessel comprising a wall,a fluid contained in the vessel, a barrier coating or layer, and apassivation layer or pH protective coating.

The wall can be a thermoplastic wall having an interior surfaceenclosing a lumen.

The fluid can be disposed in the lumen and can have a pH greater than 5.

The barrier coating or layer comprises SiO_(x), in which x is between1.5 and 2.9. The barrier coating or layer can be applied by PECVD. Thebarrier coating or layer can be positioned between the interior surfaceof the thermoplastic wall and the fluid, and supported by thethermoplastic wall. The barrier coating or layer commonly can have thecharacteristic of being subject to being measurably diminished inbarrier improvement factor in less than six months as a result of attackby the fluid, although this is not a required feature of the invention.

The passivation layer or pH protective coating comprises SiO_(x)C_(y),in which x is between 0.5 and 2.4 and y is between 0.6 and 3. Thepassivation layer or pH protective coating can be applied by PECVD, andcan be positioned between the barrier coating or layer and the fluid.The passivation layer or pH protective coating can be supported by thethermoplastic wall. The passivation layer or pH protective coating canbe effective to keep the barrier coating or layer at least substantiallyundissolved as a result of attack by the fluid for a period of at leastsix months.

Yet another aspect of the invention can be a composite materialcomprising a substrate, a barrier coating or layer over the substrate,and a passivation layer or pH protective coating (which can have thesame function as the passivation layer referred to in U.S. Pat. No.8,067,070) over the barrier coating or layer. The passivation layer orpH protective coating shows an FTIR absorbance ratio of greater than0.75 between: (1) the maximum amplitude of the Si—O—Si symmetricalstretch peak of an FTIR spectrum between about 1000 and 1040 cm⁻¹, and(2) the maximum amplitude of the Si—O—Si asymmetric stretch peak of theFTIR spectrum between about 1060 and about 1100 cm⁻¹.

Optionally, the vessel further includes an opening communicating withthe lumen and a closure. The method optionally further includes placinga fluid in the lumen via the opening and closing the opening with theclosure. The fluid can be a pharmaceutical fluid such as a drug, forexample.

Other aspects of the invention will become apparent to a person ofordinary skill in the art after reviewing the present disclosure andclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an elevation view of a capped pre-assembly according to anembodiment of the disclosure.

FIG. 2 is a longitudinal section of the capped pre-assembly of FIG. 1.

FIG. 3 is an enlarged fragmentary view of the capped pre-assembly ofFIGS. 1 and 2.

FIG. 4 is a schematic longitudinal section of the capped pre-assembly ofFIGS. 1 and 2 seated on a chemical vapor deposition coating station.

FIG. 5 is a section taken along section lines A-A of FIG. 4.

FIG. 6 is a schematic view showing more details of the chemical vapordeposition coating station shown in FIGS. 4 and 5.

FIG. 7 is a view similar to FIG. 2 of the capped pre-assembly of FIGS.1-6, filled with a pharmaceutical preparation and fitted with a plungertip, piston, stopper, or seal to define a pre-filled syringe. In theoption shown, a plunger tip, piston, stopper, or seal and plunger pushrod are installed.

FIG. 8 is a longitudinal section of a vial fitted with a septum andcrimp and having the same barrier coating or layer, passivation layer orpH protective coating, and other common features of FIG. 7.

FIG. 9 shows a SEM image of Example P. The horizontal edge-to-edge scaleis 5 μm.

FIG. 10 shows a SEM image of Example S. The horizontal edge-to-edgescale is 5 μm.

FIG. 11 shows a TEM image of a passivation layer or pH protectivecoating according to the invention coated on an SiO_(x) barrier coatingor layer, which in turn is coated on a COC substrate.

FIG. 12 shows a TEM image of an SiO₂ barrier coating or layer which iscoated on a COC substrate.

FIG. 13 is a plot of silicon dissolution versus exposure time at pH 6for a glass container versus a plastic container having an SiO_(x)barrier coating or layer coated in the inside wall.

FIG. 14 is a plot of silicon dissolution versus exposure time at pH 7for a glass container versus a plastic container having an SiO_(x)barrier coating or layer coated in the inside wall.

FIG. 15 is a plot of silicon dissolution versus exposure time at pH 8for a glass container versus a plastic container having an SiO_(x)barrier coating or layer coated in the inside wall.

FIG. 16 is a plot of the SiO_(x) coating thickness necessary initiallyto leave a 30 nm residual coating thickness when stored with solutionsat different nominal pH values from 3 to 9.

FIG. 17 shows the silicon dissolution rates at pH 8 and 40° C. ofvarious PECVD coatings.

FIG. 18 is a plot of the ratio of Si—O—Si symmetric/asymmetricstretching mode versus energy input per unit mass (W/FM or KJ/kg) of aPECVD coating using as the reactive precursor gases OMCTS and oxygen.

FIG. 19 is a plot of silicon shelf life (days) versus energy input perunit mass (W/FM or KJ/kg) of a PECVD coating using as the reactiveprecursor gases OMCTS and oxygen.

FIG. 20 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating.

FIG. 21 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating.

FIG. 22 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating.

FIG. 23 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating.

FIG. 24 is a Fourier Transform Infrared Spectrophotometer (FTIR)absorbance spectrum of a PECVD coating, originally presented as FIG. 5of U.S. Pat. No. 8,067,070, annotated to show the calculation of theO-Parameter referred to in that patent.

The following reference characters are used in the drawing figures:

12 Capped pre-assembly 14 Barrel 16 Internal wall 18 Barrel lumen 20Dispensing portion 22 Proximal opening 24 Distal opening 26 Dispensingportion lumen 27 Shield 30 Barrier coating or layer 32 Opening 34Passivation layer or pH protective coating 36 plunger tip, piston,stopper, or seal 38 Push rod 40 Fluid material 42 Rib 44 Cylindricalsurface 46 Barb 48 Catch 50 Vessel holder 52 Plot 54 Plot 60 coatingstation 82 Opening 84 Closed end 92 Vessel port 94 Vacuum duct 96 Vacuumport 98 Vacuum source 100 O-ring (of 92) 102 O-ring (of 96) 104 Gasinlet port 106 O-ring (of 100) 108 Probe (counter electrode) 110 Gasdelivery port (of 108) 114 Housing (of 50 or 112) 116 Collar 118Exterior surface (of 80) 144 PECVD gas source 152 Pressure gauge 160Electrode 162 Power supply 164 Sidewall (of 160) 166 Sidewall (of 160)168 Closed end (of 160) 200 Electrode 210 Pharmaceutical package 404Exhaust 574 Main vacuum valve 576 Vacuum line 578 Manual bypass valve580 Bypass line 582 Vent valve 584 Main reactant gas valve 586 Mainreactant feed line 588 Organosilicon liquid reservoir 590 Organosiliconfeed line (capillary) 592 Organosilicon shut-off valve 594 Oxygen tank596 Oxygen feed line 598 Mass flow controller 600 Oxygen shut-off valve602 Additional reservoir 604 Feed line 606 Shut-off valve 614 Headspace616 Pressure source 618 Pressure line 620 Capillary connection

DEFINITION SECTION

In the context of the present invention, the following definitions andabbreviations are used:

RF is radio frequency.

The term “at least” in the context of the present invention means “equalor more” than the integer following the term. The word “comprising” doesnot exclude other elements or steps, and the indefinite article “a” or“an” does not exclude a plurality unless indicated otherwise. Whenever aparameter range is indicated, it is intended to disclose the parametervalues given as limits of the range and all values of the parameterfalling within said range.

“First” and “second” or similar references to, for example, processingstations or processing devices refer to the minimum number of processingstations or devices that are present, but do not necessarily representthe order or total number of processing stations and devices. Theseterms do not limit the number of processing stations or the particularprocessing carried out at the respective stations.

For purposes of the present invention, an “organosilicon precursor” is acompound having at least one of the linkages:

which is a tetravalent silicon atom connected to an oxygen or nitrogenatom and an organic carbon atom (an organic carbon atom being a carbonatom bonded to at least one hydrogen atom). A volatile organosiliconprecursor, defined as such a precursor that can be supplied as a vaporin a PECVD apparatus, can be an optional organosilicon precursor.Optionally, the organosilicon precursor can be selected from the groupconsisting of a linear siloxane, a monocyclic siloxane, a polycyclicsiloxane, a polysilsesquioxane, an alkyl trimethoxysilane, a linearsilazane, a monocyclic silazane, a polycyclic silazane, apolysilsesquiazane, and a combination of any two or more of theseprecursors.

The feed amounts of PECVD precursors, gaseous reactant or process gases,and carrier gas are sometimes expressed in “standard volumes” in thespecification and claims. The standard volume of a charge or other fixedamount of gas is the volume the fixed amount of the gas would occupy ata standard temperature and pressure (without regard to the actualtemperature and pressure of delivery). Standard volumes can be measuredusing different units of volume, and still be within the scope of thepresent disclosure and claims. For example, the same fixed amount of gascould be expressed as the number of standard cubic centimeters, thenumber of standard cubic meters, or the number of standard cubic feet.Standard volumes can also be defined using different standardtemperatures and pressures, and still be within the scope of the presentdisclosure and claims. For example, the standard temperature might be00° C. and the standard pressure might be 760 Torr (as is conventional),or the standard temperature might be 20° C. and the standard pressuremight be 1 Torr. But whatever standard is used in a given case, whencomparing relative amounts of two or more different gases withoutspecifying particular parameters, the same units of volume, standardtemperature, and standard pressure are to be used relative to each gas,unless otherwise indicated.

The corresponding feed rates of PECVD precursors, gaseous reactant orprocess gases, and carrier gas are expressed in standard volumes perunit of time in the specification. For example, in the working examplesthe flow rates are expressed as standard cubic centimeters per minute,abbreviated as sccm. As with the other parameters, other units of timecan be used, such as seconds or hours, but consistent parameters are tobe used when comparing the flow rates of two or more gases, unlessotherwise indicated.

A “vessel” in the context of the present invention can be any type ofarticle with at least one opening and a wall defining an inner orinterior surface. The substrate can be the inside wall of a vesselhaving a lumen. Though the invention is not necessarily limited topharmaceutical packages or other vessels of a particular volume,pharmaceutical packages or other vessels are contemplated in which thelumen can have a void volume of from 0.5 to 50 mL, optionally from 1 to10 mL, optionally from 0.5 to 5 mL, optionally from 1 to 3 mL. Thesubstrate surface can be part or all of the inner or interior surfaceinner or interior surface of a vessel having at least one opening and aninner or interior surface inner or interior surface.

A vessel in the context of the present invention can have one or moreopenings. One or two openings, like the openings of a sample tube (oneopening) or a syringe barrel (two openings) are preferred. If the vesselhas two openings, they can be the same size or different sizes. If thereis more than one opening, one opening can be used for the gas inlet fora PECVD coating method according to the present invention, while theother openings are either capped or open. A vessel according to thepresent invention can be a sample tube, for example for collecting orstoring biological fluids like blood or urine, a syringe (or a partthereof, for example a syringe barrel) for storing or delivering abiologically active compound or composition, for example a medicament orpharmaceutical composition, a vial for storing biological materials orbiologically active compounds or compositions, a pipe, for example acatheter for transporting biological materials or biologically activecompounds or compositions, or a cuvette for holding fluids, for examplefor holding biological materials or biologically active compounds orcompositions.

The vessel can be provided with a reagent or preservative for samplecollection or analysis. For example, a vessel for blood collection canhave an inner or interior surface defining a lumen and an exteriorsurface, the passivation layer or pH protective coating can be on theinner or interior surface, and the vessel can contain a compound orcomposition in its lumen, for example citrate or a citrate containingcomposition.

A vessel can be of any shape, a vessel having a substantiallycylindrical wall adjacent to at least one of its open ends beingpreferred. Generally, the interior wall of the vessel can becylindrically shaped, like, for example in a sample tube or a syringebarrel. Sample tubes and syringes or their parts (for example syringebarrels) are contemplated.

A “hydrophobic layer” in the context of the present invention means thatthe coating or layer lowers the wetting tension of a surface coated withthe coating or layer, compared to the corresponding uncoated surface.Hydrophobicity can be thus a function of both the uncoated substrate andthe coating or layer. The same applies with appropriate alterations forother contexts wherein the term “hydrophobic” is used. The term“hydrophilic” means the opposite, i.e. that the wetting tension isincreased compared to reference sample. The present hydrophobic layersare primarily defined by their hydrophobicity and the process conditionsproviding hydrophobicity. Suitable hydrophobic coatings or layers andtheir application, properties, and use are described in U.S. Pat. No.7,985,188. Dual functional passivation layers or pH protective coatingsthat also have the properties of hydrophobic coatings or layers can beprovided for any embodiment of the present invention.

The values of w, x, y, and z are applicable to the empirical compositionSi_(w)O_(x)C_(y)Hz throughout this specification. The values of w, x, y,and z used throughout this specification should be understood as ratiosor an empirical formula (for example for a coating or layer), ratherthan as a limit on the number or type of atoms in a molecule. Forexample, octamethylcyclotetrasiloxane, which has the molecularcomposition Si₄O₄C₈H₂₄, can be described by the following empiricalformula, arrived at by dividing each of w, x, y, and z in the molecularformula by 4, the largest common factor: Si₁O₁C₂H₆. The values of w, x,y, and z are also not limited to integers. For example, (acyclic)octamethyltrisiloxane, molecular composition Si₃O₂C₈H₂₄, is reducible toSi₁O_(0.67)C_(2.67)H₈. Also, although SiO_(x)C_(y)H_(z) can be describedas equivalent to SiO_(x)C_(y), it is not necessary to show the presenceof hydrogen in any proportion to show the presence of SiO_(x)C_(y).

“Wetting tension” is a specific measure for the hydrophobicity orhydrophilicity of a surface. An optional wetting tension measurementmethod in the context of the present invention is ASTM D 2578 or amodification of the method described in ASTM D 2578. This method usesstandard wetting tension solutions (called dyne solutions) to determinethe solution that comes nearest to wetting a plastic film surface forexactly two seconds. This is the film's wetting tension. The procedureutilized can be varied herein from ASTM D 2578 in that the substratesare not flat plastic films, but are tubes made according to the Protocolfor Forming PET Tube and (except for controls) coated according to theProtocol for coating Tube Interior with Hydrophobic Coating or Layer(see Example 9 of EP2251671 A2).

A “lubricity coating or layer” according to the present invention is acoating or layer which has a lower frictional resistance than theuncoated surface.

A “passivation layer or pH protective coating” according to the presentinvention passivates or protects an underlying surface or layer from afluid composition contacting the layer (as more extensively definedelsewhere in this specification).

“Frictional resistance” can be static frictional resistance and/orkinetic frictional resistance.

One of the optional embodiments of the present invention can be asyringe part, for example a syringe barrel or plunger tip, piston,stopper, or seal, coated with a lubricity and/or passivation layer or pHprotective coating. In this contemplated embodiment, the relevant staticfrictional resistance in the context of the present invention is thebreakout force as defined herein, and the relevant kinetic frictionalresistance in the context of the present invention is the plungersliding force as defined herein. For example, the plunger sliding forceas defined and determined herein is suitable to determine the presenceor absence and the lubricity and/or passivating or protectivecharacteristics of a lubricity and/or passivation layer or pH protectivecoating in the context of the present invention whenever the coating orlayer is applied to any syringe or syringe part, for example to theinner wall of a syringe barrel. The breakout force can be of particularrelevance for evaluation of the coating or layer effect on a prefilledsyringe, i.e. a syringe which can be filled after coating and can bestored for some time, for example several months or even years, beforethe plunger tip, piston, stopper, or seal is moved again (has to be“broken out”).

The “plunger sliding force” (synonym to “glide force,” “maintenanceforce”, or F_(m), also used in this description) in the context of thepresent invention is the force required to maintain movement of aplunger tip, piston, stopper, or seal in a syringe barrel, for exampleduring aspiration or dispense. It can advantageously be determined usingthe ISO 7886-1:1993 test described herein and known in the art. Asynonym for “plunger sliding force” often used in the art is “plungerforce” or “pushing force”.

The “plunger breakout force” (synonym to “breakout force”, “break looseforce”, “initiation force”, Fi, also used in this description) in thecontext of the present invention is the initial force required to movethe plunger tip, piston, stopper, or seal in a syringe, for example in aprefilled syringe.

Both “plunger sliding force” and “plunger breakout force” and methodsfor their measurement are described in more detail in subsequent partsof this description. These two forces can be expressed in N, lbs or kgand all three units are used herein. These units correlate as follows:1N=0.102 kg=0.2248 lbs (pounds).

Sliding force and breakout force are sometimes used herein to describethe forces required to advance a stopper or other closure into apharmaceutical package or other vessel, such as a medical sample tube ora vial, to seat the stopper in a vessel to close the vessel. Its use canbe analogous to use in the context of a syringe and its plunger tip,piston, stopper, or seal, and the measurement of these forces for avessel and its closure are contemplated to be analogous to themeasurement of these forces for a syringe, except that at least in mostcases no liquid is ejected from a vessel when advancing the closure to aseated position.

“Slidably” means that the plunger tip, piston, stopper, or seal or otherremovable part can be permitted to slide in a syringe barrel or othervessel.

Coatings of SiO_(x) are deposited by plasma enhanced chemical vapordeposition (PECVD) or other chemical vapor deposition processes on thevessel of a pharmaceutical package, in particular a thermoplasticpackage, to serve as a barrier coating or layer preventing oxygen, air,carbon dioxide, or other gases from entering the vessel and/or toprevent leaching of the pharmaceutical material into or through thepackage wall. The barrier coating or layer can be effective to reducethe ingress of atmospheric gas, for example oxygen, into the lumencompared to a vessel without a passivation layer or pH protectivecoating.

In any embodiment the vapor-deposited coating or layer optionally canalso, or alternatively, be a solute barrier coating or layer. A concernof converting from glass to plastic syringes centers around thepotential for leachable materials from plastics. With plasma coatingtechnology, the coatings or layers derived from non-metal gaseousprecursors, for example HMDSO or OMCTS or other organosilicon compounds,will contain no trace metals and function as a barrier coating or layerto inorganic, metals and organic solutes, preventing leaching of thesespecies from the coated substrate into syringe fluids. In addition toleaching control of plastic syringes, the same plasma passivation layeror pH protective coating technology offers potential to provide a solutebarrier to the plunger tip, piston, stopper, or seal, typically made ofelastomeric plastic compositions containing even higher levels ofleachable organic oligomers and catalysts.

Moreover, certain syringes prefilled with synthetic and biologicalpharmaceutical formulations are very oxygen and moisture sensitive. Acritical factor in the conversion from glass to plastic syringe barrelswill be the improvement of plastic oxygen and moisture barrierperformance. The plasma passivation layer or pH protective coatingtechnology can be suitable to maintain the SiO_(x) barrier coating orlayer or layer for protection against oxygen and moisture over anextended shelf life.

Examples of solutes in drugs usefully excluded by a barrier layer in anyembodiment include antibacterial preservatives, antioxidants, chelatingagents, pH buffers, and combinations of any of these. In any embodimentthe vapor-deposited coating or layer optionally can be a solvent barriercoating or layer for a solvent comprising a co-solvent used to increasedrug solubilization.

In any embodiment the vapor-deposited coating or layer optionally can bea barrier coating or layer for water, glycerin, propylene glycol,methanol, ethanol, n-propanol, isopropanol, acetone, benzyl alcohol,polyethylene glycol, cotton seed oil, benzene, dioxane, or combinationsof any two or more of these.

In any embodiment the vapor-deposited coating or layer optionally can bea metal ion barrier coating or layer.

In any embodiment the vapor-deposited coating or layer optionally can bea barrel wall material barrier coating or layer, to prevent or reducethe leaching of barrel material such as any of the base barrel resinsmentioned previously and any other ingredients in their respectivecompositions.

The inventors have found, however, that such barrier coatings or layersor coatings of SiO_(x) are eroded or dissolved by some fluidcompositions, for example aqueous compositions having a pH above about5. Since coatings applied by chemical vapor deposition can be verythin—tens to hundreds of nanometers thick—even a relatively slow rate oferosion can remove or reduce the effectiveness of the barrier coating orlayer in less time than the desired shelf life of a product package.This can be particularly a problem for fluid pharmaceuticalcompositions, since many of them have a pH of roughly 7, or more broadlyin the range of 5 to 9, similar to the pH of blood and other human oranimal fluids. The higher the pH of the pharmaceutical preparation, themore quickly it erodes or dissolves the SiO_(x) coating.

The inventors have further found that without a protective coatingborosilicate glass surfaces are eroded or dissolved by some fluidcompositions, for example aqueous compositions having a pH above about5. This can be particularly a problem for fluid pharmaceuticalcompositions, since many of them have a pH of roughly 7, or more broadlyin the range of 5 to 9, similar to the pH of blood and other human oranimal fluids. The higher the pH of the pharmaceutical preparation, themore quickly it erodes or dissolves the glass. Delamination of the glasscan also result from such erosion or dissolution, as small particles ofglass are undercut by the aqueous compositions having a pH above about5.

The inventors have further found that certain passivation layers or pHprotective coatings of SiO_(x)C_(y) or SiN_(x)C_(y) formed from cyclicpolysiloxane precursors, which passivation layers or pH protectivecoatings have a substantial organic component, do not erode quickly whenexposed to fluid compositions, and in fact erode or dissolve more slowlywhen the fluid compositions have higher pHs within the range of 5 to 9.For example, at pH 8, the dissolution rate of a passivation layer or pHprotective coating made from the precursor octamethylcyclotetrasiloxane,or OMCTS, can be quite slow. These passivation layers or pH protectivecoatings of SiO_(x)C_(y) or SiN_(x)C_(y) can therefore be used to covera barrier coating or layer of SiO_(x), retaining the benefits of thebarrier coating or layer by passivating or protecting it from the fluidcomposition in the pharmaceutical package. These passivation layers orpH protective coatings of SiO_(x)C_(y) or SiN_(x)C_(y) also can be usedto cover a glass surface, for example a borosilicate glass surface,preventing delamination, erosion and dissolution of the glass, bypassivating or protecting it from the fluid composition in thepharmaceutical package.

Although the present invention does not depend upon the accuracy of thefollowing theory, it is believed that the material properties of aneffective SiO_(x)C_(y) passivation layer or pH protective coating andthose of an effective lubricity layer as described in U.S. Pat. No.7,985,188 and in International Application PCT/US11/36097 are similar insome instances, such that a coating having the characteristics of alubricity layer as described in certain working examples of thisspecification, U.S. Pat. No. 7,985,188, or International ApplicationPCT/US11/36097 will also in certain cases serve as well as a passivationlayer or pH protective coating to passivate or protect the barriercoating or layer of the package and vice versa.

Although the present invention does not depend upon the accuracy of thefollowing theory, it is further believed that the most effectivelubricity and/or passivation layers or pH protective coatings are thosemade from cyclic siloxanes and silazanes as described in thisdisclosure. SiO_(x)C_(y) or SiN_(x)C_(y) coatings deposited from linearsiloxane or linear silazane precursors, for example hexamethyldisiloxane(HMDSO), are believed to contain fragments of the original precursor toa large degree and low organic content. Such SiO_(x)C_(y) orSiN_(x)C_(y) coatings have a degree of water miscibility orswellability, allowing them to be attacked by aqueous solutions.SiO_(x)C_(y) or SiN_(x)C_(y) coatings deposited from cyclic siloxane orlinear silazane precursors, for example octamethylcyclotetrasiloxane(OMCTS), however, are believed to include more intact cyclic siloxanerings and longer series of repeating units of the precursor structure.These coatings are believed to be nanoporous but structured andhydrophobic, and these properties are believed to contribute to theirsuccess as passivation layers or pH protective coatings. This is shown,for example, in U.S. Pat. No. 7,901,783.

DETAILED DESCRIPTION

The present invention will now be described more fully, with referenceto the accompanying drawings, in which several embodiments are shown.This invention can, however, be embodied in many different forms andshould not be construed as limited to the embodiments set forth here.Rather, these embodiments are examples of the invention, which has thefull scope indicated by the language of the claims. Like numbers referto like or corresponding elements throughout. The following disclosurerelates to all embodiments unless specifically limited to a certainembodiment.

PECVD Treated Pharmaceutical Packages or Other Vessels

A vessel with a passivation layer or pH protective coating as describedherein and/or prepared according to a method described herein can beused for reception and/or storage and/or delivery of a compound orcomposition. The compound or composition can be sensitive, for exampleair-sensitive, oxygen-sensitive, sensitive to humidity and/or sensitiveto mechanical influences. It can be a biologically active compound orcomposition, for example a pharmaceutical preparation or medicament likeinsulin or a composition comprising insulin. A prefilled syringe can beespecially considered which contains injectable or other liquid drugslike insulin.

In another aspect, the compound or composition can be a biologicalfluid, optionally a bodily fluid, for example blood or a blood fraction.In certain aspects of the present invention, the compound or compositioncan be a product to be administrated to a subject in need thereof, forexample a product to be injected, like blood (as in transfusion of bloodfrom a donor to a recipient or reintroduction of blood from a patientback to the patient) or insulin.

A vessel with a passivation layer or pH protective coating as describedherein and/or prepared according to a method described herein canfurther be used for protecting a compound or composition contained inits interior space against mechanical and/or chemical effects of thesurface of the vessel material. For example, it can be used forpreventing or reducing precipitation and/or clotting or plateletactivation of the compound or a component of the composition, forexample insulin precipitation or blood clotting or platelet activation.

It can further be used for protecting a compound or compositioncontained in its interior against the environment outside of thepharmaceutical package or other vessel, for example by preventing orreducing the entry of one or more compounds from the environmentsurrounding the vessel into the interior space of the vessel. Suchenvironmental compound can be a gas or liquid, for example anatmospheric gas or liquid containing oxygen, air, and/or water vapor.

Referring to the Figures, an aspect of the invention can be a method inwhich a barrier coating or layer 30 and a passivation layer or pHprotective coating 34 are applied directly or indirectly applied to atleast a portion of the interior wall 16 of a vessel, such as any of thepharmaceutical packages 210 of FIGS. 7-8, a sample collection tube, forexample a blood collection tube and/or a closed-ended sample collectiontube; a conduit; a cuvette; or a vessel part, for example a plunger tip,piston, stopper, or seal for contact with and/or storage and/or deliveryof a compound or composition.

Vessel Wall Construction

Optionally for any of the embodiments of FIGS. 7-8, at least a portionof the internal wall 16 of the pharmaceutical package 210 comprises orconsists essentially of a polymer, for example a polyolefin (for examplea cyclic olefin polymer, a cyclic olefin copolymer, or polypropylene), apolyester, for example polyethylene terephthalate or polyethylenenaphthalate, a polycarbonate, polylactic acid, or any combination,composite or blend of any two or more of the above materials.

Optionally for any of the embodiments of FIGS. 7-8, at least a portionof the internal wall 16 of the pharmaceutical package 210 comprises orconsists essentially of glass, for example borosilicate glass.

As an optional feature of any of the foregoing embodiments the polymericmaterial can be a silicone elastomer or a thermoplastic polyurethane, astwo examples, or any material suitable for contact with blood, or withinsulin. For example, the use of a coated substrate according to anydescribed embodiment is contemplated for storing insulin.

Optionally, as for the embodiments of FIG. 7, the pharmaceutical package210 comprises a syringe barrel.

Optionally, the pharmaceutical package comprises a cartridge.

Optionally, as for the embodiments of FIG. 8, the pharmaceutical package210 comprises a vial.

Optionally, as for the embodiments of FIGS. 7-8, the pharmaceuticalpackage 210 comprises a blister package.

Optionally, the pharmaceutical package comprises an ampoule.

Alternatively, the vessel can be a length of tubing from about 1 cm toabout 200 cm, optionally from about 1 cm to about 150 cm, optionallyfrom about 1 cm to about 120 cm, optionally from about 1 cm to about 100cm, optionally from about 1 cm to about 80 cm, optionally from about 1cm to about 60 cm, optionally from about 1 cm to about 40 cm, optionallyfrom about 1 cm to about 30 cm long, and processing it with a probeelectrode as described below. Particularly for the longer lengths in theabove ranges, it is contemplated that relative motion between the PECVDor other chemical vapor deposition probe and the vessel can be usefulduring passivation layer or pH protective coating formation. This can bedone, for example, by moving the vessel with respect to the probe ormoving the probe with respect to the vessel.

In these embodiments, it is contemplated that the barrier coating orlayer discussed below can be thinner or less complete than would bepreferred to provide the high gas barrier integrity needed in anevacuated blood collection tube, and thus the long shelf life needed tostore a liquid material in contact with the barrier coating or layer foran extended period.

As an optional feature of any of the foregoing embodiments the vesselcan have a central axis. As an optional feature of any of the foregoingembodiments the vessel wall can be sufficiently flexible to be flexed atleast once at 20° C., without breaking the wall, over a range from atleast substantially straight to a bending radius at the central axis ofnot more than 100 times as great as the outer diameter of the vessel.

As an optional feature of any of the foregoing embodiments the bendingradius at the central axis can be, for example, not more than 90 timesas great as, or not more than 80 times as great as, or not more than 70times as great as, or not more than 60 times as great as, or not morethan 50 times as great as, or not more than 40 times as great as, or notmore than 30 times as great as, or not more than 20 times as great as,or not more than 10 times as great as, or not more than 9 times as greatas, or not more than 8 times as great as, or not more than 7 times asgreat as, or not more than 6 times as great as, or not more than 5 timesas great as, or not more than 4 times as great as, or not more than 3times as great as, or not more than 2 times as great as, or not morethan, the outer diameter of the vessel.

As an optional feature of any of the foregoing embodiments the vesselwall can be a fluid-contacting surface made of flexible material.

As an optional feature of any of the foregoing embodiments the vessellumen can be the fluid flow passage of a pump.

As an optional feature of any of the foregoing embodiments the vesselcan be a blood containing vessel. The passivation layer or pH protectivecoating can be effective to reduce the clotting or platelet activationof blood exposed to the inner or interior surface, compared to the sametype of wall uncoated with a hydrophobic layer.

It is contemplated that the incorporation of a hydrophobic layer willreduce the adhesion or clot forming tendency of the blood, as comparedto its properties in contact with an unmodified polymeric or SiO_(x)surface. This property is contemplated to reduce or potentiallyeliminate the need for treating the blood with heparin, as by reducingthe necessary blood concentration of heparin in a patient undergoingsurgery of a type requiring blood to be removed from the patient andthen returned to the patient, as when using a heart-lung machine duringcardiac surgery. It is contemplated that this will reduce thecomplications of surgery involving the passage of blood through such apharmaceutical package or other vessel, by reducing the bleedingcomplications resulting from the use of heparin.

Another embodiment can be a vessel including a wall and having an inneror interior surface defining a lumen. The inner or interior surface canhave an at least partial passivation layer or pH protective coating thatpresents a hydrophobic surface, the thickness of the passivation layeror pH protective coating being from monomolecular thickness to about1000 nm thick on the inner or interior surface, the passivation layer orpH protective coating being effective to reduce the clotting or plateletactivation of blood exposed to the inner or interior surface.

Several non-limiting examples of such a vessel are a blood transfusionbag, a blood sample collection vessel in which a sample has beencollected, the tubing of a heart-lung machine, a flexible-walled bloodcollection bag, or tubing used to collect a patient's blood duringsurgery and reintroduce the blood into the patient's vasculature. If thevessel includes a pump for pumping blood, a particularly suitable pumpcan be a centrifugal pump or a peristaltic pump. The vessel can have awall; the wall can have an inner or interior surface defining a lumen.The inner or interior surface of the wall can have an at least partialpassivation layer or pH protective coating of a protective layer, whichoptionally also presents a hydrophobic surface. The passivation layer orpH protective coating can be as thin as monomolecular thickness or asthick as about 1000 nm. Optionally, the vessel can contain blood viablefor return to the vascular system of a patient disposed within the lumenin contact with the hydrophobic layer.

An embodiment can be a blood containing vessel including a wall andhaving an inner or interior surface defining a lumen. The inner orinterior surface can have an at least partial passivation layer or pHprotective coating that optionally also presents a hydrophobic surface.The passivation layer or pH protective coating can also comprise orconsist essentially of SiO_(x)C_(y) where x and y are as defined in thisspecification. The vessel contains blood viable for return to thevascular system of a patient disposed within the lumen in contact withthe hydrophobic coating or layer.

An embodiment can be carried out under conditions effective to form ahydrophobic passivation layer or pH protective coating on the substrate.Optionally, the hydrophobic characteristics of the passivation layer orpH protective coating can be set by setting the ratio of the oxidizinggas to the organosilicon precursor in the gaseous reactant, and/or bysetting the electric power used for generating the plasma. Optionally,the passivation layer or pH protective coating can have a lower wettingtension than the uncoated surface, optionally a wetting tension of from20 to 72 dyne/cm, optionally from 30 to 60 dynes/cm, optionally from 30to 40 dynes/cm, optionally 34 dyne/cm. Optionally, the passivation layeror pH protective coating can be more hydrophobic than the uncoatedsurface.

In an optional embodiment, the vessel can have an inner diameter of atleast 2 mm, or at least 4 mm.

As an optional feature of any of the foregoing embodiments the vesselcan be a tube.

As an optional feature of any of the foregoing embodiments the lumen canhave at least two open ends.

Syringe

The vessel of FIGS. 1-7 is a syringe, which is a contemplated type ofvessel provided with a passivation layer or pH protective coating. Thesyringe can comprise a syringe barrel 14 and a plunger tip, piston,stopper, or seal 36. The internal wall 16 can define at least a portionof the syringe barrel 250. The plunger tip, piston, stopper, or seal 36can be a relatively sliding part of the syringe, with respect to thesyringe barrel 250. The term “syringe” is broadly defined to includecartridges, injection “pens,” and other types of barrels or reservoirsadapted to be assembled with one or more other components to provide afunctional syringe. A “syringe” is also broadly defined to includerelated articles such as auto-injectors, which provide a mechanism fordispensing the contents.

As one non-limiting way to make the syringe, a capped pre-assembly 12can be provided comprising a barrel 14, a dispensing portion 20, and ashield 28. The capped pre-assembly 12 can be a complete article or itcan be a portion of a complete article adapted to dispense fluid, suchas a syringe, a cartridge, a catheter, or other article.

The barrel 14 can have an internal wall 16 defining a barrel lumen 18.Optionally in any embodiment, the barrel 14 can further include anopening 32 spaced from the dispensing portion 20 and communicatingthrough the internal wall 16. Such an opening can be conventional, forexample, in a syringe or cartridge, where a typical example can be theback opening 32 of a prefilled syringe barrel, through which the plungertip, piston, stopper, or seal 36 can be inserted after the barrel lumen18 is filled with a suitable pharmaceutical preparation or other fluidmaterial 40 to be dispensed.

The barrel 14 can be formed, for example, by molding, although themanner of its formation is not critical and it can also be formed, forexample, by machining a solid preform. Preferably, the barrel can bemolded by injection molding thermoplastic material, although it can alsobe formed by blow molding or a combined method.

As one preferred example, the barrel 14 can be formed by placing adispensing portion 20 as described below in an injection mold andinjection molding thermoplastic material about the dispensing portion,thus forming the barrel and securing the dispensing portion to thebarrel. Alternatively, the dispensing portion and the barrel can bemolded or otherwise formed as a single piece, or can be formedseparately and joined in other ways. The barrel of any embodiment can bemade of any suitable material. Several barrel materials particularlycontemplated are COC (cyclic olefin copolymer), COP (cyclic olefinpolymer), PET (polyethylene terephthalate), and polypropylene.

The dispensing portion 20 of the capped pre-assembly 12 can be providedto serve as an outlet for fluid dispensed from the barrel lumen 18 of acompleted article made from the capped pre-assembly 12. One example of asuitable dispensing portion illustrated in the Figures can be ahypodermic needle 20.

Alternatively, in any embodiment the dispensing portion 20 can insteadbe a needle-free dispenser. One example of a suitable needle-freedispenser can be a blunt or flexible dispensing portion intended to bereceived in a complementary coupling to transfer fluid material 40. Suchblunt or flexible dispensing portions are well known for use insyringes, intravenous infusion systems, and other systems and equipmentto dispense material while avoiding the hazard of working with a sharpneedle that may accidentally stick a health professional or otherperson. Another example of a needle-free dispenser can be a fluid jet orspray injection system that injects a free jet or spray of fluiddirectly through a patient's skin, without the need for an intermediateneedle. Any type of dispensing portion 20, whether a hypodermic needleor any form of needle-free dispenser, is contemplated for use accordingto any embodiment of the present invention.

The dispensing portion 20 is or can be secured to the barrel 14 andincludes a proximal opening 22, a distal opening 24, and a dispensingportion lumen 26. The proximal opening 22 communicates with the barrellumen 18. The distal opening 24 can be located outside the barrel 14.The dispensing portion lumen 26 communicates between the proximal anddistal openings 22, 24 of the dispensing portion 20. In the illustratedembodiment, the distal opening 24 can be at the sharpened tip of ahypodermic needle 20.

The shield 28 can be secured to the barrel 14 and at least substantiallyisolates the distal opening 24 of the dispensing portion 20 frompressure conditions outside the shield 28. Optionally in any embodiment,the shield 28 sufficiently isolates portions of the assembly 12 toprovide a sufficient bio-barrier to facilitate safe use of the cappedpre-assembly 12 for transdermal injections.

The shield 28 can isolate the distal opening 24 in various ways.Effective isolation can be provided at least partially due to contactbetween the shield 28 and the distal opening 24, as shown in presentFIGS. 2, 3, 4, and 7. In the illustrated embodiment, the tip of thedispensing portion 20 can be buried in the material of the shield 28.Alternatively in any embodiment, effective isolation can be provided atleast partially due to contact between the shield 28 and the barrel 14,as also shown in present FIGS. 2, 3, 4, and 7. In the illustratedembodiment, the primary line of contact between the shield 28 and thebarrel 14 can be at a rib 42 (best seen in FIG. 3) encircling and seatedagainst a generally cylindrical surface 44 at the nose of the barrel 14.Alternatively in any embodiment, effective isolation can be provided dueto both of these types of contact as illustrated in FIGS. 2-3, or inother ways, without limitation.

The shield 28 of any embodiment optionally can have a latchingmechanism, best shown in FIG. 3, including a barb 46 and a catch 48which engage to hold the shield 28 in place. The catch 48 can be made ofsufficiently resilient material to allow the shield 28 to be removed andreplaced easily.

If the dispensing portion 20 is a hypodermic needle, the shield 28 canbe a specially formed needle shield. The original use of a needle shieldis to cover the hypodermic needle before use, preventing accidentalneedle sticks and preventing contamination of the needle before it isinjected in a patient or an injection port. A comparable shieldpreferably is used, even if the dispensing portion 20 is a needle-freedispenser, to prevent contamination of the dispenser during handling.

The shield 28 can be formed in any suitable way. For example, the shield28 can be formed by molding thermoplastic material. Optionally in anyembodiment, the thermoplastic material can be elastomeric material orother material that can be suitable for forming a seal. One suitablecategory of elastomeric materials is known generically as thermoplasticelastomer (TPE). An example of a suitable thermoplastic elastomer formaking a shield 28 is Stelmi® Formulation 4800 (flexible shieldformulation). Any other material having suitable characteristics caninstead be used in any embodiment.

As another optional feature in any embodiment the shield 28 can besufficiently permeable to a sterilizing gas to sterilize the portions ofthe assembly 12 isolated by the shield. One example of a suitablesterilizing gas is ethylene oxide. Shields 28 are available that aresufficiently permeable to the sterilizing gas that parts isolated by theshield can nonetheless be sterilized. An example of a shield formulationsufficiently permeable to accommodate ethylene oxide gas sterilizationcan be Stelmi® Formulation 4800.

Three embodiments of the invention having many common features are thoseof FIGS. 7-8. Some of their common features are the following, indicatedin many cases by common reference characters or names. The nature of thefeatures of each embodiment can be as described later in thespecification.

The pharmaceutical packages of FIGS. 7-8 each include a vessel 210, afluid composition 40, an SiO_(x) barrier coating or layer 30, and apassivation layer or pH protective coating 34. Each vessel 210 can havea lumen 18 defined at least in part by a wall interior portion 16 madeof thermoplastic material.

The internal wall 16 can have an interior surface 254 facing the lumen18 and an outer surface 216.

The fluid composition 40 can be contained in the lumen 18 and can have apH between 4 and 10, alternatively between 5 and 9.

Barrier Coating or Layer

In the filled pharmaceutical package or other vessel 210 the barriercoating or layer 30 can be located between the inner or interior surfaceof the thermoplastic internal wall 16 and the fluid material 40. Thebarrier coating or layer 286 of SiO_(x) can be supported by thethermoplastic internal wall 16. The barrier coating or layer 286 canhave the characteristic of being subject to being measurably diminishedin barrier improvement factor in less than six months as a result ofattack by the fluid material 40. The barrier coating or layer 286 asdescribed elsewhere in this specification, or in U.S. Pat. No.7,985,188, can be used in any embodiment.

The barrier coating or layer 30 can be effective to reduce the ingressof atmospheric gas into the lumen 18, compared to an uncoated containerotherwise the same as the pharmaceutical package or other vessel 210.The barrier coating or layer for any embodiment defined in thisspecification (unless otherwise specified in a particular instance) isoptionally applied by PECVD as indicated in U.S. Pat. No. 7,985,188.

The barrier improvement factor (BIF) of the barrier coating or layer canbe determined by providing two groups of identical containers, adding abarrier coating or layer to one group of containers, testing a barrierproperty (such as the rate of outgassing in micrograms per minute oranother suitable measure) on containers having a barrier coating orlayer, doing the same test on containers lacking a barrier coating orlayer, and taking a ratio of the properties of the materials with versuswithout a barrier coating or layer. For example, if the rate ofoutgassing through the barrier coating or layer is one-third the rate ofoutgassing without a barrier coating or layer, the barrier coating orlayer has a BIF of 3.

The barrier coating or layer optionally can be characterized as an“SiO_(x)” coating, and contains silicon, oxygen, and optionally otherelements, in which x, the ratio of oxygen to silicon atoms, can be fromabout 1.5 to about 2.9, or 1.5 to about 2.6, or about 2. Thesealternative definitions of x apply to any use of the term SiO_(x) inthis specification. The barrier coating or layer can be applied, forexample to the interior of a pharmaceutical package or other vessel, forexample a sample collection tube, a syringe barrel, a vial, or anothertype of vessel.

The barrier coating or layer 30 comprises or consists essentially ofSiO_(x), from 2 to 1000 nm thick, the barrier coating or layer 30 ofSiO_(x) having an interior surface facing the lumen 18 and an outersurface facing the internal wall 16. The barrier coating or layer 30 canbe effective to reduce the ingress of atmospheric gas into the lumen 18compared to an uncoated pharmaceutical package 210. One suitable barriercomposition can be one where x is 2.3, for example.

For example, the barrier coating or layer such as 30 of any embodimentcan be applied at a thickness of at least 2 nm, or at least 4 nm, or atleast 7 nm, or at least 10 nm, or at least 20 nm, or at least 30 nm, orat least 40 nm, or at least 50 nm, or at least 100 nm, or at least 150nm, or at least 200 nm, or at least 300 nm, or at least 400 nm, or atleast 500 nm, or at least 600 nm, or at least 700 nm, or at least 800nm, or at least 900 nm. The barrier coating or layer can be up to 1000nm, or at most 900 nm, or at most 800 nm, or at most 700 nm, or at most600 nm, or at most 500 nm, or at most 400 nm, or at most 300 nm, or atmost 200 nm, or at most 100 nm, or at most 90 nm, or at most 80 nm, orat most 70 nm, or at most 60 nm, or at most 50 nm, or at most 40 nm, orat most 30 nm, or at most 20 nm, or at most 10 nm, or at most 5 nmthick. Specific thickness ranges composed of any one of the minimumthicknesses expressed above, plus any equal or greater one of themaximum thicknesses expressed above, are expressly contemplated. Thethickness of the SiO_(x) or other barrier coating or layer can bemeasured, for example, by transmission electron microscopy (TEM), andits composition can be measured by X-ray photoelectron spectroscopy(XPS). The passivation layer or pH protective coating described hereincan be applied to a variety of pharmaceutical packages or other vesselsmade from plastic or glass, for example to plastic tubes, vials, andsyringes.

Passivation Layer or pH Protective Coating

A passivation layer or pH protective coating 34 of SiO_(x)C_(y) can beapplied, for example, by PECVD directly or indirectly to the barriercoating or layer 30 so it can be located between the barrier coating orlayer 30 and the fluid material 40 in the finished article. Thepassivation layer or pH protective coating 34 can have an interiorsurface facing the lumen 18 and an outer surface facing the interiorsurface of the barrier coating or layer 30. The passivation layer or pHprotective coating 34 can be supported by the thermoplastic internalwall 16. The passivation layer or pH protective coating 34 can beeffective to keep the barrier coating or layer 30 at least substantiallyundissolved as a result of attack by the fluid material 40 for a periodof at least six months, in one non-limiting embodiment.

Optionally, the passivation layer or pH protective coating can becomposed of Si_(w)O_(x)C_(y)H_(z) (or its equivalent SiO_(x)C_(y)) orSi_(w)N_(x)C_(y)H_(z) or its equivalent SiN_(x)C_(y)), each as definedin this specification. Taking into account the H atoms, the passivationlayer or pH protective coating may thus in one aspect have the formulaSi_(w)O_(x)C_(y)H_(z), or its equivalent SiO_(x)C_(y), for example wherew is 1, x is from about 0.5 to about 2.4, y is from about 0.6 to about3, and z (if defined) is from about 2 to about 9.

The atomic ratio can be determined by XPS (X-ray photoelectronspectroscopy). XPS does not detect hydrogen atoms, so it is customary,when determining the atomic ratio by XPS, to omit hydrogen from thestated formulation. The formulation thus can be typically expressed asSi_(w)O_(x)C_(y), where w is 1, x is from about 0.5 to about 2.4, and yis from about 0.6 to about 3, with no limitation on z.

The atomic ratios of Si, O, and C in the “lubricity and/or passivationlayer or pH protective coating” can be, as several options:

Si 100: O 50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2);

Si 100: O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to 2)

Si 100: O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9 to 1.5)

Si 100: O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to 1.4), or

Si 100: O 92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to 1.33)

Typically, such a coating or layer would contain 36% to 41% carbonnormalized to 100% carbon plus oxygen plus silicon. Alternatively, thepassivation layer or pH protective coating can have atomicconcentrations normalized to 100% carbon, oxygen, and silicon, asdetermined by X-ray photoelectron spectroscopy (XPS) of less than 50%carbon and more than 25% silicon. Alternatively, the atomicconcentrations can be from 25 to 45% carbon, 25 to 65% silicon, and 10to 35% oxygen. Alternatively, the atomic concentrations can be from 30to 40% carbon, 32 to 52% silicon, and 20 to 27% oxygen. Alternatively,the atomic concentrations can be from 33 to 37% carbon, 37 to 47%silicon, and 22 to 26% oxygen.

Optionally, the atomic concentration of carbon in the protective layer,normalized to 100% of carbon, oxygen, and silicon, as determined byX-ray photoelectron spectroscopy (XPS), can be greater than the atomicconcentration of carbon in the atomic formula for the organosiliconprecursor. For example, embodiments are contemplated in which the atomicconcentration of carbon increases by from 1 to 80 atomic percent,alternatively from 10 to 70 atomic percent, alternatively from 20 to 60atomic percent, alternatively from 30 to 50 atomic percent,alternatively from 35 to 45 atomic percent, alternatively from 37 to 41atomic percent.

Optionally, the atomic ratio of carbon to oxygen in the passivationlayer or pH protective coating can be increased in comparison to theorganosilicon precursor, and/or the atomic ratio of oxygen to siliconcan be decreased in comparison to the organosilicon precursor.

Optionally, the passivation layer or pH protective coating can have anatomic concentration of silicon, normalized to 100% of carbon, oxygen,and silicon, as determined by X-ray photoelectron spectroscopy (XPS),less than the atomic concentration of silicon in the atomic formula forthe feed gas. For example, embodiments are contemplated in which theatomic concentration of silicon decreases by from 1 to 80 atomicpercent, alternatively by from 10 to 70 atomic percent, alternatively byfrom 20 to 60 atomic percent, alternatively by from 30 to 55 atomicpercent, alternatively by from 40 to 50 atomic percent, alternatively byfrom 42 to 46 atomic percent.

As another option, a passivation layer or pH protective coating iscontemplated that can be characterized by a sum formula wherein theatomic ratio C:O can be increased and/or the atomic ratio Si:O can bedecreased in comparison to the sum formula of the organosiliconprecursor.

The passivation layer or pH protective coating can have a densitybetween 1.25 and 1.65 g/cm³, alternatively between 1.35 and 1.55 g/cm³,alternatively between 1.4 and 1.5 g/cm³, alternatively between 1.4 and1.5 g/cm³, alternatively between 1.44 and 1.48 g/cm³, as determined byX-ray reflectivity (XRR). Optionally, the organosilicon compound can beoctamethylcyclotetrasiloxane and the passivation layer or pH protectivecoating can have a density which can be higher than the density of apassivation layer or pH protective coating made from HMDSO as theorganosilicon compound under the same PECVD reaction conditions.

The passivation layer or pH protective coating optionally can have anRMS surface roughness value (measured by AFM) of from about 2 to about9, optionally from about 6 to about 8, optionally from about 6.4 toabout 7.8. The R_(a) surface roughness value of the passivation layer orpH protective coating, measured by AFM, can be from about 4 to about 6,optionally from about 4.6 to about 5.8. The R_(max) surface roughnessvalue of the passivation layer or pH protective coating, measured byAFM, can be from about 70 to about 160, optionally from about 84 toabout 142, optionally from about 90 to about 130.

The rate of erosion, dissolution, or leaching (different names forrelated concepts) of the construction including a passivation layer orpH protective coating 34, if directly contacted by the fluid material40, can be less than the rate of erosion, dissolution, or leaching ofthe barrier coating or layer 30, if directly contacted by the fluidmaterial 40.

The passivation layer or pH protective coating 34 can be effective toisolate or protect the barrier coating or layer 30 from the fluidmaterial 40 at least for sufficient time to allow the barrier coating orlayer to act as a barrier during the shelf life of the pharmaceuticalpackage or other vessel 210.

Optionally an FTIR absorbance spectrum of the passivation layer or pHprotective coating 34 of any embodiment of FIGS. 7-8 can have a ratiogreater than 0.75 between the maximum amplitude of the Si—O—Sisymmetrical stretch peak normally located between about 1000 and 1040cm⁻¹, and the maximum amplitude of the Si—O—Si asymmetric stretch peaknormally located between about 1060 and about 1100 cm⁻¹. Alternativelyin any embodiment, this ratio can be at least 0.8, or at least 0.9, orat least 1.0, or at least 1.1, or at least 1.2. Alternatively in anyembodiment, this ratio can be at most 1.7, or at most 1.6, or at most1.5, or at most 1.4, or at most 1.3. Any minimum ratio stated here canbe combined with any maximum ratio stated here, as an alternativeembodiment of the invention of FIGS. 7-8.

Optionally, in any embodiment of FIGS. 7-8 the passivation layer or pHprotective coating, in the absence of the medicament, can have anon-oily appearance. This appearance has been observed in some instancesto distinguish an effective passivation layer or pH protective coatingfrom a lubricity layer, which in some instances has been observed tohave an oily (i.e. shiny) appearance.

Optionally, in any embodiment of FIGS. 7-8 the silicon dissolution rateby a 50 mM potassium phosphate buffer diluted in water for injection,adjusted to pH 8 with concentrated nitric acid, and containing 0.2 wt. %polysorbate-80 surfactant, (measured in the absence of the medicament,to avoid changing the dissolution reagent), at 40° C., can be less than170 ppb/day. (Polysorbate-80 is a common ingredient of pharmaceuticalpreparations, available for example as Tween®-80 from Uniqema AmericasLLC, Wilmington Del.) As will be seen from the working examples, thesilicon dissolution rate can be measured by determining the totalsilicon leached from the vessel into its contents, and does notdistinguish between the silicon derived from the passivation layer or pHprotective coating 34, the lubricity layer 287, the barrier coating orlayer 30, or other materials present.

Optionally, in any embodiment of FIGS. 7-8 the silicon dissolution ratecan be less than 160 ppb/day, or less than 140 ppb/day, or less than 120ppb/day, or less than 100 ppb/day, or less than 90 ppb/day, or less than80 ppb/day. Optionally, in any embodiment of FIGS. 7-8 the silicondissolution rate can be more than 10 ppb/day, or more than 20 ppb/day,or more than 30 ppb/day, or more than 40 ppb/day, or more than 50ppb/day, or more than 60 ppb/day. Any minimum rate stated here can becombined with any maximum rate stated here, as an alternative embodimentof the invention of FIGS. 7-8.

Optionally, in any embodiment of FIGS. 7-8 the total silicon content ofthe passivation layer or pH protective coating and barrier coating orlayer, upon dissolution into a test composition with a pH of 8 from thevessel, can be less than 66 ppm, or less than 60 ppm, or less than 50ppm, or less than 40 ppm, or less than 30 ppm, or less than 20 ppm.

Optionally, in any embodiment of FIGS. 7-8 the calculated shelf life ofthe package (total Si/Si dissolution rate) can be more than six months,or more than 1 year, or more than 18 months, or more than 2 years, ormore than 2½ years, or more than 3 years, or more than 4 years, or morethan 5 years, or more than 10 years, or more than 20 years. Optionally,in any embodiment of FIGS. 7-8 the calculated shelf life of the package(total Si/Si dissolution rate) can be less than 60 years.

Any minimum time stated here can be combined with any maximum timestated here, as an alternative embodiment of the invention of FIGS. 7-8.

O-Parameter or P-Parameters of Passivation Coating or Protective Layer

The passivation layer or pH protective coating 34 optionally can have anO-Parameter measured with attenuated total reflection (ATR) of less than0.4, measured as:

${O\text{-}{Parameter}} = {\frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 1253\mspace{14mu}{cm}^{- 1}}{{Maximum}\mspace{14mu}{intensity}\mspace{14mu}{in}\mspace{14mu}{the}\mspace{14mu}{range}\mspace{14mu} 1000\mspace{14mu}{to}\mspace{14mu} 1100\mspace{14mu}{cm}^{- 1}}.}$The O-Parameter is defined in U.S. Pat. No. 8,067,070, which claims anO-parameter value of most broadly from 0.4 to 0.9. It can be measuredfrom physical analysis of an FTIR amplitude versus wave number plot tofind the numerator and denominator of the above expression, as shown inFIG. 24, which is the same as FIG. 5 of U.S. Pat. No. 8,067,070, exceptannotated to show interpolation of the wave number and absorbance scalesto arrive at an absorbance at 1253 cm⁻¹ of 0.0424 and a maximumabsorbance at 1000 to 1100 cm⁻¹ of 0.08, resulting in a calculatedO-parameter of 0.53. The O-Parameter can also be measured from digitalwave number versus absorbance data.

U.S. Pat. No. 8,067,070 asserts that its claimed O-parameter rangeprovides a superior passivation layer or pH protective coating, relyingon experiments only with HMDSO and HMDSN, which are both non-cyclicsiloxanes. Surprisingly, it has been found by the present inventors thatif the PECVD precursor is a cyclic siloxane, for example OMCTS,O-parameters outside the ranges claimed in U.S. Pat. No. 8,067,070,using OMCTS, can provide better results than are obtained in U.S. Pat.No. 8,067,070 with HMDSO.

Alternatively in the embodiment of FIGS. 7-8, the O-parameter can have avalue of from 0.1 to 0.39, or from 0.15 to 0.37, or from 0.17 to 0.35.

Even another aspect of the invention can be a composite material as justdescribed, exemplified in FIGS. 7-8, wherein the passivation layer or pHprotective coating shows an N-Parameter measured with attenuated totalreflection (ATR) of less than 0.7, measured as:

${N\text{-}{Parameter}} = {\frac{{Intensity}\mspace{14mu}{at}\mspace{14mu} 840\mspace{14mu}{cm}^{- 1}}{{Intensity}\mspace{14mu}{at}\mspace{14mu} 799\mspace{14mu}{cm}^{- 1}}.}$The N-Parameter is also described in U.S. Pat. No. 8,067,070, and can bemeasured analogously to the O-Parameter except that intensities at twospecific wave numbers are used—neither of these wave numbers is a range.U.S. Pat. No. 8,067,070 claims a passivation layer or pH protectivecoating with an N-Parameter of 0.7 to 1.6. Again, the present inventorshave made better coatings employing a passivation layer or pH protectivecoating 34 having an N-Parameter lower than 0.7, as described above.Alternatively, the N-parameter can have a value of 0.3 to lower than0.7, or from 0.4 to 0.6, or from at least 0.53 to lower than 0.7.Theory of Operation

The inventors offer the following theory of operation of the passivationlayer or pH protective coating described here. The invention is notlimited by the accuracy of this theory or to the embodiments predictableby use of this theory.

The dissolution rate of the SiO_(x) barrier coating or layer, or ofglass, is believed to be dependent on SiO bonding within the layer orglass. Oxygen bonding sites (silanols) are believed to increase thedissolution rate.

It is believed that the OMCTS-based passivation layer or pH protectivecoating bonds with the silanol sites on the SiO_(x) barrier coating orlayer, or glass, to “heal” or passivate the SiO_(x) surface or glass andthus dramatically reduce the dissolution rate. In this hypothesis, thethickness of the OMCTS layer is not the primary means of protection—theprimary means can be passivation of the SiO_(x) or glass surface. It iscontemplated that a passivation layer or pH protective coating asdescribed in this specification can be improved by increasing thecrosslink density of the passivation layer or pH protective coating.

Optional Graded Composite Layers

The passivation layer or pH protective coating 34 and lubricity layersof any embodiment of FIGS. 7-8 can be either separate layers with asharp transition or a single, graduated layer that transitions betweenthe passivation layer or pH protective coating 34 and the lubricitylayer, without a sharp interface between them. Another optionalexpedient contemplated here, for adjacent layers of SiO_(x) and apassivation layer or pH protective coating, can be a graded composite ofSiO_(x) and Si_(w)O_(x)C_(y), or its equivalent SiO_(x)C_(y), as definedin the Definition Section.

A graded composite can be separate layers of a lubricity and/orprotective and/or barrier coating or layer or coating with a transitionor interface of intermediate composition between them, or separatelayers of a lubricity and/or protective and/or hydrophobic layer andSiO_(x) with an intermediate distinct passivation layer or pH protectivecoating of intermediate composition between them, or a single coating orlayer that changes continuously or in steps from a composition of alubricity and/or protective and/or hydrophobic layer to a compositionmore like SiO_(x), going through the passivation layer or pH protectivecoating in a normal direction.

The grade in the graded composite can go in either direction. Forexample, the composition of SiO_(x) can be applied directly to thesubstrate and graduate to a composition further from the surface of apassivation layer or pH protective coating, and optionally can furthergraduate to another type of coating or layer, such as a hydrophobiccoating or layer or a lubricity coating or layer. Additionally, in anyembodiment an adhesion coating or layer, for example Si_(w)O_(x)C_(y),or its equivalent SiO_(x)C_(y), optionally can be applied directly tothe substrate before applying the barrier coating or layer.

A graduated passivation layer or pH protective coating is particularlycontemplated if a layer of one composition is better for adhering to thesubstrate than another, in which case the better-adhering compositioncan, for example, be applied directly to the substrate. It iscontemplated that the more distant portions of the graded passivationlayer or pH protective coating can be less compatible with the substratethan the adjacent portions of the graded passivation layer or pHprotective coating, since at any point the passivation layer or pHprotective coating can be changing gradually in properties, so adjacentportions at nearly the same depth of the passivation layer or pHprotective coating have nearly identical composition, and more widelyphysically separated portions at substantially different depths can havemore diverse properties. It is also contemplated that a passivationlayer or pH protective coating portion that forms a better barrieragainst transfer of material to or from the substrate can be directlyagainst the substrate, to prevent the more remote passivation layer orpH protective coating portion that forms a poorer barrier from beingcontaminated with the material intended to be barred or impeded by thebarrier.

The applied coatings or layers, instead of being graded, optionally canhave sharp transitions between one layer and the next, without asubstantial gradient of composition. Such passivation layer or pHprotective coating can be made, for example, by providing the gases toproduce a layer as a steady state flow in a non-plasma state, thenenergizing the system with a brief plasma discharge to form a coating orlayer on the substrate. If a subsequent passivation layer or pHprotective coating is to be applied, the gases for the previouspassivation layer or pH protective coating are cleared out and the gasesfor the next passivation layer or pH protective coating are applied in asteady-state fashion before energizing the plasma and again forming adistinct layer on the surface of the substrate or its outermost previouspassivation layer or pH protective coating, with little if any gradualtransition at the interface.

PECVD Apparatus

The low-pressure PECVD process described in U.S. Pat. No. 7,985,188 canbe used to provide the barrier coating or layer, lubricity coating orlayer, and/or passivation layer or pH protective coating described inthis specification. A brief synopsis of that process follows, withreference to present FIGS. 4-6.

A PECVD apparatus or coating station 60 suitable for the present purposeincludes a vessel holder 50, an inner electrode defined by the probe108, an outer electrode 160, and a power supply 162. The pre-assembly 12seated on the vessel holder 50 defines a plasma reaction chamber, whichoptionally can be a vacuum chamber. Optionally, a source of vacuum 98, areactant gas source 144, a gas feed (probe 108) or a combination of twoor more of these can be supplied.

The PECVD apparatus can be used for atmospheric-pressure PECVD, in whichcase the plasma reaction chamber defined by the pre-assembly 12 does notneed to function as a vacuum chamber.

Referring to FIGS. 4-6, the vessel holder 50 comprises a gas inlet port104 for conveying a gas into the pre-assembly 12 seated on the opening82. The gas inlet port 104 can have a sliding seal provided for exampleby at least one O-ring 106, or two O-rings in series, or three O-ringsin series, which can seat against a cylindrical probe 108 when the probe108 is inserted through the gas inlet port 104. The probe 108 can be agas inlet conduit that extends to a gas delivery port at its distal end110. The distal end 110 of the illustrated embodiment can be inserted atan appropriate depth in the pre-assembly 12 for providing one or morePECVD reactants and other precursor feed or process gases.

FIG. 6 shows additional optional details of the coating station 60 thatare usable, for example, with all the illustrated embodiments. Thecoating station 60 can also have a main vacuum valve 574 in its vacuumline 576 leading to the pressure sensor 152. A manual bypass valve 578can be provided in the bypass line 580. A vent valve 582 controls flowat the vent 404.

Flow out of the PECVD gas or precursor source 144 can be controlled by amain reactant gas valve 584 regulating flow through the main reactantfeed line 586. One component of the gas source 144 can be theorganosilicon liquid reservoir 588, containing the precursor. Thecontents of the reservoir 588 can be drawn through the organosiliconcapillary line 590, which optionally can be provided at a suitablelength to provide the desired flow rate. Flow of organosilicon vapor canbe controlled by the organosilicon shut-off valve 592. Pressure can beapplied to the headspace 614 of the liquid reservoir 588, for example apressure in the range of 0-15 psi (0 to 78 cm. Hg), from a pressuresource 616 such as pressurized air connected to the headspace 614 by apressure line 618 to establish repeatable organosilicon liquid deliverythat is not dependent on atmospheric pressure (and the fluctuationstherein). The reservoir 588 can be sealed and the capillary connection620 can be at the bottom of the reservoir 588 to ensure that only neatorganosilicon liquid (not the pressurized gas from the headspace 614)flows through the capillary tube 590. The organosilicon liquidoptionally can be heated above ambient temperature, if necessary ordesirable to cause the organosilicon liquid to evaporate, forming anorganosilicon vapor. To accomplish this heating, the apparatus canadvantageously include heated delivery lines from the exit of theprecursor reservoir to as close as possible to the gas inlet into thesyringe. Preheating can be useful, for example, when feeding OMCTS.

Oxidant gas can be provided from the oxidant gas tank 594 via an oxidantgas feed line 596 controlled by a mass flow controller 598 and providedwith an oxidant shut-off valve 600.

Optionally in any embodiment, other precursor, oxidant, and/or carriergas reservoirs such as 602 can be provided to supply additionalmaterials if needed for a particular deposition process. Each suchreservoir such as 602 can have an appropriate feed line 604 and shut-offvalve 606.

Referring especially to FIG. 4, the processing station 60 can include anelectrode 160 fed by a radio frequency power supply 162 for providing anelectric field for generating plasma within the pre-assembly 12 duringprocessing. In this embodiment, the probe 108 can be electricallyconductive and can be grounded, thus providing a counter-electrodewithin the pre-assembly 12. Alternatively, in any embodiment the outerelectrode 160 can be grounded and the probe 108 can be directlyconnected to the power supply 162.

In the embodiment of FIGS. 4-6, the outer electrode 160 can either begenerally cylindrical as illustrated in FIGS. 4 and 5 or a generallyU-shaped elongated channel as illustrated in FIG. 6 (FIG. 5 being analternative embodiment of the section taken along section line A-A ofFIG. 4). Each illustrated embodiment can have one or more sidewalls,such as 164 and 166, and optionally a top end 168, disposed about thepre-assembly 12 in close proximity.

Application of Barrier Coating or Layer

When carrying out the present method, a barrier coating or layer 30 canbe applied directly or indirectly to at least a portion of the internalwall 16 of the barrel 14. In the illustrated embodiment, the barriercoating or layer 30 can be applied while the pre-assembly 12 is capped,though this is not a requirement. The barrier coating or layer 30 can bean SiO_(x) barrier coating or layer applied by plasma enhanced chemicalvapor deposition (PECVD), under conditions substantially as described inU.S. Pat. No. 7,985,188. The barrier coating or layer 30 can be appliedunder conditions effective to maintain communication between the barrellumen 18 and the dispensing portion lumen 26 via the proximal opening 22at the end of the applying step.

In any embodiment the barrier coating or layer 30 optionally can beapplied through the opening 32.

In any embodiment the barrier coating or layer 30 optionally can beapplied by introducing a vapor-phase precursor material through theopening and employing chemical vapor deposition to deposit a reactionproduct of the precursor material on the internal wall of the barrel.

In any embodiment the precursor material for forming the barrier coatingoptionally can be any of the precursors described in U.S. Pat. No.7,985,188 or in this specification for formation of the passivatinglayer or pH protective coating.

In any embodiment the reactant vapor material optionally can comprise anoxidant gas.

In any embodiment the reactant vapor material optionally can compriseoxygen.

In any embodiment the reactant vapor material optionally can comprise acarrier gas.

In any embodiment the reactant vapor material optionally can includehelium, argon, krypton, xenon, neon, or a combination of two or more ofthese.

In any embodiment the reactant vapor material optionally can includeargon.

In any embodiment the reactant vapor material optionally can be aprecursor material mixture with one or more oxidant gases and a carriergas in a partial vacuum through the opening and employing chemical vapordeposition to deposit a reaction product of the precursor materialmixture on the internal wall of the barrel.

In any embodiment the reactant vapor material optionally can be passedthrough the opening at sub-atmospheric pressure.

In any embodiment plasma optionally can be generated in the barrel lumen18 by placing an inner electrode into the barrel lumen 18 through theopening 32, placing an outer electrode outside the barrel 14 and usingthe electrodes to apply plasma-inducing electromagnetic energy whichoptionally can be radio frequency energy, in the barrel lumen 18. If adifferent arrangement is used, the plasma-inducing electromagneticenergy can be microwave energy or other forms of electromagnetic energy.

In any embodiment the electromagnetic energy optionally can be directcurrent.

In any embodiment the electromagnetic energy optionally can bealternating current. The alternating current optionally can be modulatedat frequencies including audio, or microwave, or radio, or a combinationof two or more of audio, microwave, or radio.

In any embodiment the electromagnetic energy optionally can be appliedacross the barrel lumen (18).

Application of Passivation Layer or pH Protective Coating

In any embodiment, in addition to applying a first coating or layer asdescribed above, the method optionally can include applying second orfurther coating or layer of the same material or a different material.As one example useful in any embodiment, particularly contemplated ifthe first coating or layer is an SiO_(x) barrier coating or layer, afurther coating or layer can be placed directly or indirectly over thebarrier coating or layer. One example of such a further coating or layeruseful in any embodiment is a passivation layer or pH protective coating34.

Precursors

The organosilicon precursor for any of the processes for forming thebarrier coating or layer, the passivation layer or pH protectivecoating, or a lubricity coating or layer can include any of thefollowing precursors.

The precursor for the passivation layer or pH protective coating of thepresent invention is broadly defined as an organometallic precursor. Anorganometallic precursor is defined in this specification ascomprehending compounds of metal elements from Group III and/or Group IVof the Periodic Table having organic residues, for example hydrocarbon,aminocarbon or oxycarbon residues. Organometallic compounds as presentlydefined include any precursor having organic moieties bonded to siliconor other Group III/IV metal atoms directly, or optionally bonded throughoxygen or nitrogen atoms. The relevant elements of Group III of thePeriodic Table are Boron, Aluminum, Gallium, Indium, Thallium, Scandium,Yttrium, and Lanthanum, Aluminum and Boron being preferred. The relevantelements of Group IV of the Periodic Table are Silicon, Germanium, Tin,Lead, Titanium, Zirconium, Hafnium, and Thorium, with Silicon and Tinbeing preferred. Other volatile organic compounds can also becontemplated. However, organosilicon compounds are preferred forperforming present invention.

An organosilicon precursor is contemplated, where an “organosiliconprecursor” is defined throughout this specification most broadly as acompound having at least one of the linkages:

The first structure immediately above is a tetravalent silicon atomconnected to an oxygen atom and an organic carbon atom (an organiccarbon atom being a carbon atom bonded to at least one hydrogen atom).The second structure immediately above is a tetravalent silicon atomconnected to an —NH— linkage and an organic carbon atom (an organiccarbon atom being a carbon atom bonded to at least one hydrogen atom).

Optionally, the organosilicon precursor can be selected from the groupconsisting of a linear siloxane, a monocyclic siloxane, a polycyclicsiloxane, a polysilsesquioxane, a linear silazane, a monocyclicsilazane, a polycyclic silazane, a polysilsesquiazane, and a combinationof any two or more of these precursors. Also contemplated as aprecursor, though not within the two formulas immediately above, can bean alkyl trimethoxysilane.

If an oxygen-containing precursor (for example a Siloxane) is used, arepresentative predicted empirical composition resulting from PECVDunder conditions forming a hydrophobic or lubricating passivation layeror pH protective coating would be Si_(w)O_(x)C_(y)H_(z) or itsequivalent SiO_(x)C_(y) as defined in the Definition Section, while arepresentative predicted empirical composition resulting from PECVDunder conditions forming a barrier coating or layer would be SiO_(x),where x in this formula is from about 1.5 to about 2.9. If anitrogen-containing precursor (for example a silazane) is used, thepredicted composition would be Si_(w)*N_(x)*C_(y)*H_(z)*, i.e. inSi_(w)O_(x)C_(y)H_(z) or its equivalent SiO_(x)C_(y) as specified in theDefinition Section, O is replaced by N and the indices for H are adaptedto the higher valency of N as compared to O (3 instead of 2). The latteradaptation will generally follow the ratio of w, x, y and z in aSiloxane to the corresponding indices in its aza counterpart. In aparticular aspect of the invention, Si_(w*)N_(x*)C_(y*)H_(z*) (or itsequivalent SiN_(x)*C_(y)*) in which w*, x*, y*, and z* are defined thesame as w, x, y, and z for the siloxane counterparts, but for anoptional deviation in the number of hydrogen atoms.

One type of precursor starting material having the above empiricalformula can be a linear siloxane, for example a material having thefollowing formula:

in which each R can be independently selected from alkyl, for examplemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl,alkyne, or others, and n can be 1, 2, 3, 4, or greater, optionally twoor greater. Several examples of contemplated linear siloxanes arehexamethyldisiloxane (HMDSO) (particularly for forming the barriercoating or layer 30 of a vessel),octamethyltrisiloxane,decamethyltetrasiloxane,dodecamethylpentasiloxane,or combinations of two or more of these. The analogous silazanes inwhich —NH— can be substituted for the oxygen atom in the above structureare also useful for making analogous passivation layers or pH protectivecoatings or layers. Several examples of contemplated linear silazanesare octamethyltrisilazane, decamethyltetrasilazane, or combinations oftwo or more of these.

Another type of precursor starting material, among the preferredstarting materials in the present context, can be a monocyclic siloxane,for example a material having the following structural formula:

in which R can be defined as for the linear structure and “a” can befrom 3 to about 10, or the analogous monocyclic silazanes. Severalexamples of contemplated hetero-substituted and unsubstituted monocyclicsiloxanes and silazanes include:1,3,5-trimethyl-1,3,5-tris(3,3,3-trifluoropropyl)methyl]cyclotrisiloxane2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane,pentamethylcyclopentasiloxane,pentavinylpentamethylcyclopentasiloxane,hexamethylcyclotrisiloxane,hexaphenylcyclotrisiloxane (HMCTS,octamethylcyclotetrasiloxane (OMCTS),decamethylcyclopentasiloxane (DMCPS),2,2,4,4,6,6,8,8-octamethyl-1,5-dimethano-3,7-dioxa-2,4,6,8-tetrasiloxaneoctaphenylcyclotetrasiloxane,decamethylcyclopentasiloxanedodecamethylcyclohexasiloxane,methyl(3,3,3-trifluoropropl)cyclosiloxane,Cyclic organosilazanes are also contemplated, such asOctamethylcyclotetrasilazane,1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasilazanehexamethylcyclotrisilazane,octamethylcyclotetrasilazane,decamethylcyclopentasilazane,dodecamethylcyclohexasilazane, orcombinations of any two or more of these.

Another type of precursor starting material, among the preferredstarting materials in the present context, can be a polycyclic siloxane,for example a material having one of the following structural formulas:

in which Y can be oxygen or nitrogen, E is silicon, and Z is a hydrogenatom or an organic substituent, for example alkyl such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others.When each Y is oxygen, the respective structures, from left to right,are a Silatrane, a Silquasilatrane, and a Silproatrane. When Y isnitrogen, the respective structures are an azasilatrane, anazasilquasiatrane, and an azasilproatrane.

Another type of polycyclic siloxane precursor starting material, amongthe preferred starting materials in the present context, can be apolysilsesquioxane, with the empirical formula RSiO_(1.5) and thestructural formula:

in which each R is a hydrogen atom or an organic substituent, forexample alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, vinyl, alkyne, or others. Two commercial materials of this sortare SST-eM01 poly(methylsilsesquioxane), in which each R can be methyl,and SST-3MH1.1 poly(Methyl-Hydridosilsesquioxane), in which 90% of the Rgroups are methyl, 10% are hydrogen atoms. This material is available ina 10% solution in tetrahydrofuran, for example. Combinations of two ormore of these are also contemplated. Other examples of a contemplatedprecursor are methylsilatrane, CAS No. 2288-13-3, in which each Y isoxygen and Z is methyl, methylazasilatrane, poly(methylsilsesquioxane)(for example SST-eM01 poly(methylsilsesquioxane)), in which each Roptionally can be methyl, SST-3MH1.1 poly(Methyl-Hydridosilsesquioxane)(for example SST-3MH1.1 poly(Methyl-Hydridosilsesquioxane)), in which90% of the R groups are methyl and 10% are hydrogen atoms, or acombination of any two or more of these.

The analogous polysilsesquiazanes in which —NH— can be substituted forthe oxygen atom in the above structure are also useful for makinganalogous passivation layer or pH protective coating. Examples ofcontemplated polysilsesquiazanes are a poly(methylsilsesquiazane), inwhich each R can be methyl, and a poly(Methyl-Hydridosilsesquiazane, inwhich 90% of the R groups are methyl, 10% are hydrogen atoms.Combinations of two or more of these are also contemplated.

One particularly contemplated precursor for the barrier coating or layeraccording to the present invention can be a linear siloxane, for examplehexamethyldisiloxane or HMDSO. One particularly contemplated precursorfor the lubricity coating or layer and the passivation layer or pHprotective coating according to the present invention can be a cyclicsiloxane, for example octamethylcyclotetrasiloxane (OMCTS).

It is believed that the OMCTS or other cyclic siloxane molecule providesseveral advantages over other siloxane materials. First, its ringstructure is believed to result in a less dense passivation layer or pHprotective coating (as compared to passivation layer or pH protectivecoating prepared from HMDSO). The molecule also is believed to allowselective ionization so that the final structure and chemicalcomposition of the passivation layer or pH protective coating can bedirectly controlled through the application of the plasma power. Otherorganosilicon molecules are readily ionized (fractured) so that it canbe more difficult to retain the original structure of the molecule.

In any of the PECVD methods according to the present invention, theapplying step optionally can be carried out by vaporizing the precursorand providing it in the vicinity of the substrate. For example, OMCTScan be vaporized by heating it to about 50° C. before applying it to thePECVD apparatus.

Cyclic organosilicon precursors, in particular monocyclic organosiliconprecursors (like the monocyclic precursors listed elsewhere in presentdescription), and specifically OMCTS, are particularly suitable toachieve a passivation layer or pH protective coating.

The organosilicon precursor can be delivered at a rate of equal to orless than 10 sccm, optionally equal to or less than 6 sccm, optionallyequal to or less than 2.5 sccm, optionally equal to or less than 1.5sccm, optionally equal to or less than 1.25 sccm. Larger pharmaceuticalpackages or other vessels or other changes in conditions or scale mayrequire more or less of the precursor.

Other Components of PECVD Reaction Mixture and Ratios of Components forPassivation Layer or pH Protective Coating

Generally, for a passivation layer or pH protective coating, O₂ can bepresent in an amount (which can, for example be expressed by the flowrate in sccm) which can be less than one order of magnitude greater thanthe organosilicon amount. In contrast, in order to achieve a barriercoating or layer, the amount of 02 typically can be at least one orderof magnitude higher than the amount of organosilicon precursor.

As some specific examples of suitable proportions of the respectiveconstituents, the volume ratio (in sccm) of organosilicon precursor toO₂ for a passivation layer or pH protective coating can be in the rangefrom 0.1:1 to 10:1, optionally in the range from 0.3:1 to 8:1,optionally in the range from 0.5:1 to 5:1, optionally from 1:1 to 3:1.Some non-exhaustive alternative selections and suitable proportions ofthe precursor gas, oxygen, and a carrier gas are provided below.

The process gas can contain this ratio of gases for preparing alubricity and/or passivation layer or pH protective coating:

from 0.5 to 10 standard volumes of the precursor;

from 1 to 100 standard volumes of a carrier gas,

from 0.1 to 10 standard volumes of an oxidizing agent.

alternatively this ratio:

from 1 to 6 standard volumes of the precursor;

from 1 to 80 standard volumes of a carrier gas,

from 0.1 to 2 standard volumes of an oxidizing agent.

alternatively this ratio:

from 2 to 4 standard volumes, of the precursor;

from 1 to 100 standard volumes of a carrier gas,

from 0.1 to 2 standard volumes of an oxidizing agent.

alternatively this ratio:

from 1 to 6 standard volumes of the precursor;

from 3 to 70 standard volumes, of a carrier gas,

from 0.1 to 2 standard volumes of an oxidizing agent.

alternatively this ratio:

-   -   from 2 to 4 standard volumes, of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   2 to 4 standard volumes, of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 10 to 70 standard volumes, of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 10 to 70 standard volumes, of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   2 to 4 standard volumes, of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.

Exemplary reaction conditions for preparing a passivation layer or pHprotective coating according to the present invention in a 3 ml samplesize syringe with a ⅛″ diameter tube (open at the end) are as follows:

Flow Rate Ranges:

OMCTS: 0.5-10 sccm

Oxygen: 0.1-10 sccm

Argon: 1.0-200 sccm

Power: 0.1-500 watts

In another contemplated embodiment the proportions of precursor, oxygen,and Argon can be, for example:

OMCTS: 0.5-5.0 sccm

Oxygen: 0.1-5.0 sccm

Argon: 1.0-20 sccm

In yet another contemplated embodiment the proportions of precursor,oxygen, and Argon and the power level can be, for example:

Specific Flow rates:

OMCTS: 2.0 sccm

Oxygen: 0.7 sccm

Argon: 7.0 sccm

Power: 3.5 watts

The coatings can vary from the above proportions, however. For example,to provide a coating with lubricity which also serves as a passivationlayer or pH protection coating, the following proportions of gases canbe used:

-   -   from 0.5 to 10 standard volumes, optionally from 1 to 6 standard        volumes, optionally from 2 to 4 standard volumes, optionally        equal to or less than 6 standard volumes, optionally equal to or        less than 2.5 standard volumes, optionally equal to or less than        1.5 standard volumes, optionally equal to or less than 1.25        standard volumes of the precursor, for example OMCTS or one of        the other precursors of any embodiment;    -   from 0 to 100 standard volumes, optionally from 1 to 80 standard        volumes, optionally from 5 to 100 standard volumes, optionally        from 10 to 70 standard volumes, of a carrier gas of any        embodiment;    -   from 0.1 to 10 standard volumes, optionally from 0.1 to 2        standard volumes, optionally from 0.2 to 1.5 standard volumes,        optionally from 0.2 to 1 standard volumes, optionally from 0.5        to 1.5 standard volumes, optionally from 0.8 to 1.2 standard        volumes of an oxidizing agent.

The presence of the precursor and O₂ in the volume ratios as given inTables 9-11 can be specifically suitable to achieve a passivation layeror pH protective coating.

In one aspect of the invention, a carrier gas can be absent in thereaction mixture; in another aspect of the invention, it can be present.Suitable carrier gases include any noble gas, for example Argon, Helium,Neon, Xenon or combinations of two or more of these. When the carriergas is present in the reaction mixture, it is typically present in avolume (in sccm) exceeding the volume of the organosilicon precursor.For example, the ratio of the organosilicon precursor to carrier gas canbe from 1:1 to 1:50, optionally from 1:5 to 1:40, optionally from 1:10to 1:30. One function of the carrier gas can be to dilute the reactantsin the plasma, encouraging the formation of a coating on the substrateinstead of powdered reaction products that do not adhere to thesubstrate and are largely removed with the exhaust gases.

The addition of Argon gas has been found to improve the performance ofthe passivation layer or pH protective coating 34. It is believed thatadditional ionization of the molecule in the presence of Argoncontributes to this performance. The Si—O—Si bonds of the molecule havea high bond energy followed by the Si—C, with the C—H bonds being theweakest. Passivation or pH protection appear to be achieved when aportion of the C—H bonds are broken. This allows the connecting(cross-linking) of the structure as it grows. Addition of oxygen (withthe Argon) is understood to enhance this process. A small amount ofoxygen can also provide C—O bonding to which other molecules can bond.The combination of breaking C—H bonds and adding oxygen all at lowpressure and power leads to a chemical structure that can be solid whileproviding passivation or pH protection.

In any of the disclosed embodiments, one preferred combination ofprocess gases includes octamethylcyclotetrasiloxane (OMCTS) or anothercyclic siloxane as the precursor; O₂, nitrous oxide (N₂O), ozone (O₃),or another oxidizing gas, which means any other gas that oxidizes theprecursor during PECVD at the conditions employed, preferably O₂; and acarrier gas, for example a noble carrier gas, for example Argon (Ar).The gaseous reactant or process gas can be at least substantially freeof nitrogen. This combination is contemplated to improve the resultingpassivation layer or pH protective coating.

Application Method

A passivation layer or pH protective coating 34 optionally can beapplied directly or indirectly over the barrier coating or layer 30, andoptionally can be applied to a pre-assembly such as 12 while thepre-assembly is capped, under conditions effective to maintaincommunication between the barrel lumen 18 and the dispensing portionlumen 26 via the proximal opening 22 at the end of applying thepassivation layer or pH protective coating 34.

Vessel Made of Glass

Optionally in any embodiment, the passivation layer or pH protectivecoating 34 can be applied as the first or sole vapor-deposited coatingor layer 30, instead of or in addition to its application as a furtherlayer. This expedient may be useful, for example, where the barrel ismade of glass, as described below. The presently disclosed passivationlayer or pH protective coating also can reduce the dissolution of glassby contents having the pH values indicated as attacking SiO_(x) coatingsor layers.

A pharmaceutical package 210 is contemplated as shown in any embodiment,for example FIGS. 7-8, comprising a vessel or vessel part made of glass;optionally a barrier coating or layer or layer such as 30 on the vesselor vessel part; a passivation layer or pH protective coating such as 34on the vessel, vessel part, or barrier coating or layer or layer; and apharmaceutical composition or preparation contained within the vessel.

In this glass embodiment the barrier coating or layer or layer can beoptional because a glass vessel wall in itself is an extremely goodbarrier coating or layer. It is contemplated to optionally provide abarrier coating or layer primarily to provide isolation: in other words,to prevent contact and interchange of material of any kind, such as ionsof the glass or constituents of the pharmaceutical composition orpreparation between the vessel wall and the contents of the vessel. Theprotective layer as defined in this specification can be contemplated toperform the isolation function independently, at least to a degree. Thispassivation coating or pH protection layer can be contemplated toprovide a useful function on glass in contact with the pharmaceuticalcomposition or preparation, as the present working examples show thatborosilicate glass, commonly used today for pharmaceutical packaging,can be dissolved by a fluid composition having a pH exceeding 5.Particularly in applications where such dissolution can bedisadvantageous or perceived to be disadvantageous, the presentpassivation layers or protective coatings or layers will find utility.

The vessel can be made, for example of glass of any type used in medicalor laboratory applications, such as soda-lime glass, borosilicate glass,or other glass formulations. One function of a passivation layer or pHprotective coating on a glass vessel can be to reduce the ingress ofions in the glass, either intentionally or as impurities, for examplesodium, calcium, or others, from the glass to the contents of thepharmaceutical package or other vessel, such as a reagent or blood in anevacuated blood collection tube. Alternatively, a dual functionalprotective/lubricity coating or layer can be used on a glass vessel inwhole or in part, such as selectively at surfaces contacted in slidingrelation to other parts, to provide lubricity, for example to ease theinsertion or removal of a stopper or passage of a sliding element suchas a piston in a syringe, as well as to provide the isolation of apassivation layer or pH protective coating. Still another reason to coata glass vessel, for example with a dual functional hydrophobic andpassivation layer or pH protective coating, can be to prevent a reagentor intended sample for the pharmaceutical package or other vessel, suchas blood, from sticking to the wall of the vessel or an increase in therate of coagulation of the blood in contact with the wall of the vessel,as well as to provide the isolation of a passivation layer or pHprotective coating.

A related embodiment can be a vessel as described in the previousparagraphs, in which the barrier coating or layer or layer can be madeof soda lime glass, borosilicate glass, or another type of glass coatingor layer on a substrate.

Plasma Conditions for Passivation Layer or pH Protective Coating

The precursor can be contacted with a plasma made by energizing thevicinity of the precursor with electrodes powered at radio frequency,optionally a frequency of 10 kHz to 2.45 GHz, optionally from 10 kHz toless than 300 MHz, optionally from 1 to 50 MHz, optionally from 10 to 15MHz, alternatively from about 13 to about 14 MHz, optionally at or about13.56 MHz. Typically, the plasma in the PECVD process can be generatedat RF frequency, although microwave or other electromagnetic energy canalso be used. For providing a protective layer on the interior of avessel by a plasma reaction carried out within the vessel, the plasma ofany embodiment can be generated with an electric power of from 0.1 to500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300 W,optionally from 1 to 250 W, optionally from 1 to 200 W, even optionallyfrom 10 to 150 W, optionally from 20 to 150 W, for example of 40 W,optionally from 40 to 150 W, even optionally from 60 to 150 W.

For any PECVD process in any embodiment herein, PECVD can be initiatedby applying an initial higher power level within the stated range,followed by a subsequent lower power level within the stated range. Theinitial higher power level can be applied, for example, for from 1 to 3seconds. The subsequent lower power level can applied, for example, forthe remainder of PECVD.

For forming a coating intended to provide lubricity in addition topassivation or pH protection, the precursor can be contacted with aplasma made by energizing the vicinity of the precursor with electrodessupplied with electric power at from 0.1 to 25 W, optionally from 1 to22 W, optionally from 1 to 10 W, even optionally from 1 to 5 W,optionally from 2 to 4 W, for example of 3 W, optionally from 3 to 17 W,even optionally from 5 to 14 W, for example 6 or 7.5 W, optionally from7 to 11 W, for example of 8 W.

The ratio of the electrode power to the plasma volume can be less than100 W/ml, optionally can be from 0.1 to 100 W/mL, optionally can be from5 W/ml to 75 W/ml, optionally can be from 6 W/ml to 60 W/ml, optionallycan be from 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml.These power levels are suitable for applying passivation layers orprotective coatings or layers to syringes and sample tubes andpharmaceutical packages or other vessels of similar geometry having avoid volume of 5 mL in which PECVD plasma can be generated. It iscontemplated that for larger or smaller objects the power applied, inWatts, should be increased or reduced accordingly to scale the processto the size of the substrate.

For forming a coating intended to provide lubricity in addition topassivation or pH protection, the precursor can be contacted with aplasma made by energizing the vicinity of the precursor with electrodessupplied with electric power density at less than 10 W/ml of plasmavolume, alternatively from 6 W/ml to 0.1 W/ml of plasma volume,alternatively from 5 W/ml to 0.1 W/ml of plasma volume, alternativelyfrom 4 W/ml to 0.1 W/ml of plasma volume, alternatively from 2 W/ml to0.2 W/ml of plasma volume, alternatively from 10 W/ml to 50 W/ml,optionally from 20 W/ml to 40 W/ml.

Optionally, in any embodiment of FIGS. 7-8 the passivation layer or pHprotective coating can be applied by PECVD at a power level per of morethan 22,000 kJ/kg of mass of precursor, or more than 30,000 kJ/kg ofmass of precursor, or more than 40,000 kJ/kg of mass of precursor, ormore than 50,000 kJ/kg of mass of precursor, or more than 60,000 kJ/kgof mass of precursor, or more than 62,000 kJ/kg of mass of precursor, ormore than 70,000 kJ/kg of mass of precursor, or more than 80,000 kJ/kgof mass of precursor, or more than 100,000 kJ/kg of mass of precursor,or more than 200,000 kJ/kg of mass of precursor, or more than 300,000kJ/kg of mass of precursor, or more than 400,000 kJ/kg of mass ofprecursor, or more than 500,000 kJ/kg of mass of precursor.

Optionally, in any embodiment of FIGS. 7-8 the passivation layer or pHprotective coating 34 can be applied by PECVD at a power level per ofless than 2,000,000 kJ/kg of mass of precursor, or less than 1,000,000kJ/kg of mass of precursor, or less than 700,000 kJ/kg of mass ofprecursor, or less than 500,000 kJ/kg of mass of precursor, or less than100,000 kJ/kg of mass of precursor, or less than 90,000 kJ/kg of mass ofprecursor, or less than 81,000 kJ/kg of mass of precursor.

For a PECVD process the deposition time can be from 1 to 30 sec,alternatively from 2 to 10 sec, alternatively from 3 to 9 sec. Thepurposes for optionally limiting deposition time can be to avoidoverheating the substrate, to increase the rate of production, and toreduce the use of process gas and its constituents. The purposes foroptionally extending deposition time can be to provide a thickerpassivation layer or pH protective coating for particular depositionconditions.

Other methods can be used to apply the passivation layer or pHprotective coating. For example, hexamethylene disilazane (HMDZ) can beused as the precursor. HMDZ has the advantage of containing no oxygen inits molecular structure. This passivation layer or pH protective coatingtreatment is contemplated to be a surface treatment of the SiO_(x)barrier coating or layer with HMDZ. It is contemplated that HMDZ willreact with the —OH sites that are present in the silicon dioxidecoating, resulting in the evolution of NH₃ and bonding of S—(CH₃)₃ tothe silicon (it is contemplated that hydrogen atoms will be evolved andbond with nitrogen from the HMDZ to produce NH₃).

It is contemplated that this HMDZ passivation layer or pH protectivecoating can be accomplished through several possible paths.

One contemplated path can be dehydration/vaporization of the HMDZ atambient temperature. First, an SiO_(x) surface can be deposited, forexample using hexamethylene disiloxane (HMDSO). The as-coated silicondioxide surface then can be reacted with HMDZ vapor. In an embodiment,as soon as the SiO_(x) surface is deposited onto the article ofinterest, the vacuum can be maintained. The HMDSO and oxygen are pumpedaway and a base vacuum is achieved. Once base vacuum is achieved, HMDZvapor can be flowed over the surface of the silicon dioxide (as coatedon the part of interest) at pressures from the mTorr range to many Torr.The HMDZ then can be pumped away (with the resulting NH₃ that is abyproduct of the reaction). The amount of NH₃ in the gas stream can bemonitored (with a residual gas analyzer—RGA—as an example) and whenthere is no more NH₃ detected, the reaction is complete. The part thencan be vented to atmosphere (with a clean dry gas or nitrogen). Theresulting surface then can be found to have been passivated orprotected. It is contemplated that this method optionally can beaccomplished without forming a plasma.

Alternatively, after formation of the SiO_(x) barrier coating or layer,the vacuum can be broken before dehydration/vaporization of the HMDZ.Dehydration/vaporization of the HMDZ can then be carried out in eitherthe same apparatus used for formation of the SiO_(x) barrier coating orlayer or different apparatus.

Dehydration/vaporization of HMDZ at an elevated temperature is alsocontemplated. The above process can alternatively be carried out at anelevated temperature exceeding room temperature up to about 150° C. Themaximum temperature can be determined by the material from which thecoated part is constructed. An upper temperature should be selected thatwill not distort or otherwise damage the part being coated.

Dehydration/vaporization of HMDZ with a plasma assist is alsocontemplated. After carrying out any of the above embodiments ofdehydration/vaporization, once the HMDZ vapor is admitted into the part,plasma can be generated. The plasma power can range from a few watts to100+ watts (similar powers as used to deposit the SiO_(x)). The above isnot limited to HMDZ and could be applicable to any molecule that willreact with hydrogen, for example any of the nitrogen-containingprecursors described in this specification.

Surprisingly, it has been found that the above stated coatings or layerscan be applied to the capped pre-assembly 12 with substantially nodeposition of the vapor-deposited coating 30 in the dispensing portionlumen 26. This is shown by a working example below.

In certain embodiments, the generation of uniform plasma throughout theportion of the vessel to be coated is contemplated, as it has been foundin certain instances to generate a better passivation layer or pHprotective coating. Uniform plasma means regular plasma that does notinclude a substantial amount of hollow cathode plasma (which has higheremission intensity than regular plasma and can be manifested as alocalized area of higher intensity interrupting the more uniformintensity of the regular plasma).

It is further contemplated that any embodiment of the passivation layeror pH protective coating processes described in this specification canalso be carried out without using the article to be coated to containthe plasma. For example, external surfaces of medical devices, forexample catheters, surgical instruments, closures, and others can bepassivated or protected by sputtering the coating, employing a radiofrequency target.

Non-Organosilicon Passivation Layer or pH Protective Coating

Another way of applying the passivation layer or pH protective coatingcan be to apply as the passivation layer or pH protective coating anamorphous carbon or fluorinated polymer coating, or a combination of thetwo.

Amorphous carbon coatings can be formed by PECVD using a saturatedhydrocarbon, (e.g. methane, ethane, ethylene or propane), or anunsaturated hydrocarbon (e.g. ethylene, acetylene), or a combination oftwo or more of these as a precursor for plasma polymerization.

Fluorinated polymer coatings can be applied by chemically modifying aprecursor, while on or in the vicinity of the fluid receiving interiorsurface.

Optionally, the precursor comprises:

-   -   dimeric tetrafluoroparaxylylene,    -   difluorocarbene,    -   monomeric tetrafluoroethylene,    -   oligomeric tetrafluoroethylene having the formula F2C═CF(CF2)xF        in which x can be from 1 to 100, optionally 2 to 50, optionally        2-20, optionally 2-10,    -   sodium chlorodifluoroacetate,    -   chlorodifluoromethane,    -   bromodifluoromethane,    -   hexafluoropropylene oxide,    -   1H,1H,2H,2H-perfluorodecyl acrylate (FDA),    -   a bromofluoroalkane in which the alkane moiety can have from 1        to 6 carbon atoms,    -   an iodofluoroalkane in which the alkane moiety can have from 1        to 6 carbon atoms, or    -   a combination of any two or more of these.

The fluorinated polymer is:

-   -   optionally from at least 0.01 micrometer to at most 100        micrometers thick,    -   optionally from at least 0.05 micrometers to at most 90        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 80        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 70        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 60        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 50        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 40        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 30        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 20        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 15        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 12        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 10        micrometers thick    -   optionally from at least 0.1 micrometers to at most 8        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 6        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 4        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 2        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 1        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 0.9        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 0.8        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 0.7        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 0.6        micrometers thick,    -   optionally from at least 0.1 micrometers to at most 0.5        micrometers thick,    -   optionally from at least 0.5 micrometers to at most 5        micrometers thick,    -   optionally from at least 0.5 micrometers to at most 4        micrometers thick,    -   optionally from at least 0.5 micrometers to at most 3        micrometers thick,    -   optionally from at least 0.5 micrometers to at most 2        micrometers thick,    -   optionally from at least 0.5 micrometers to at most 1 micrometer        thick,    -   optionally about 10 micrometers thick,    -   optionally about 2 micrometers thick.

The fluorinated polymer optionally can be applied by vapor deposition,for example chemical vapor deposition. Optionally, the fluorinatedpolymer can be applied by chemical vapor deposition of dimerictetrafluoroparaxylylene. An example of a suitable fluorinated polymercan be polytetrafluoroparaxylylene. Optionally, the fluorinated polymerconsists essentially of polytetrafluoroparaxylylene.

Optionally in any embodiment, the fluorinated polymer coating or layercomprises polytetrafluoroethylene. Optionally in any embodiment, thefluorinated polymer coating or layer consists essentially ofpolytetrafluoroethylene.

For example, in any embodiment, the fluorinated polymer coating or layercan be applied by chemically modifying a precursor, while on or in thevicinity of the fluid receiving interior surface, to produce thefluorinated polymer coating or layer on the fluid receiving interiorsurface. Optionally in any embodiment, the fluorinated polymer coatingor layer can be applied by chemical vapor deposition. For one example,in any embodiment, the fluorinated polymer coating or layer can beapplied by heated wire chemical vapor deposition (HWCVD). For anotherexample, in any embodiment, the fluorinated polymer coating or layer canbe applied by plasma enhanced chemical vapor deposition (PECVD). Mixedprocesses or other processes for applying a suitable coating are alsocontemplated, in any embodiment.

Another example of a suitable HWCVD process for applying the fluorinatedpolymer coating can be the process described in Hilton G. Pryce Lewis,Neeta P. Bansal, Aleksandr J. White, Erik S. Handy, HWCVD of Polymers:Commercialization and Scale-up, THIN SOLID FILMS 517 2009) 3551-3554; USPubl. Appl. 2012/0003497 A1, published Jan. 5, 2012; and US Publ. Appl.2011/0186537, published Aug. 4, 2011, which are incorporated here byreference in their entirety for their description of fluorinated polymercoatings and their application.

It is contemplated that that amorphous carbon and/or fluorinated polymercoatings will provide better passivation or protection of an SiO_(x)barrier coating or layer than a siloxane coating since an amorphouscarbon and/or fluorinated polymer coating will not contain silanolbonds.

It is further contemplated that fluorosilicon precursors can be used toprovide a passivation layer or pH protective coating over an SiO_(x)barrier coating or layer. This can be carried out by using as aprecursor a fluorinated silane precursor such as hexafluorosilane and aPECVD process. The resulting coating would also be expected to be anon-wetting coating.

Liquid-Applied Passivation Layer or pH Protective Coating

Another example of a suitable barrier or other type of passivation layeror pH protective coating, usable in conjunction with the PECVD-appliedpassivation layer or pH protective coating or other PECVD treatment asdisclosed here, can be a liquid barrier, lubricant, surface energytailoring, or passivation layer or pH protective coating 90 applied tothe inner or interior surface of a pharmaceutical package or othervessel, either directly or with one or more intervening PECVD-appliedcoatings or layers described in this specification, for example SiO_(x),a lubricity coating or layer and/or a passivation layer or pH protectivecoating, or both.

A suitable liquid barrier, lubricity, or passivation layer or pHprotective coating 90 also optionally can be applied, for example, byapplying a liquid monomer or other polymerizable or curable material tothe inner or interior surface of the vessel 80 and curing, polymerizing,or crosslinking the liquid monomer to form a solid polymer, or byapplying a solvent-dispersed polymer to the surface 88 and removing thesolvent.

Any of the above methods can include as a step forming a passivationlayer or pH protective coating 90 on the interior 88 of a vessel 80 viathe vessel port 92 at a processing station or device 28. One example canbe applying a liquid passivation layer or pH protective coating, forexample of a curable monomer, prepolymer, or polymer dispersion, to theinner or interior surface 88 of a vessel 80 and curing it to form a filmthat physically isolates the contents of the vessel 80 from its inner orinterior surface 88. The prior art describes polymer passivation layeror pH protective coating technology as suitable for treating plasticblood collection tubes. For example, the acrylic and polyvinylidenechloride (PVdC) passivation layer or pH protective coating materials andmethods described in U.S. Pat. No. 6,165,566, which is herebyincorporated by reference, optionally can be used.

Any of the above methods can also include as a step forming a coating orlayer on the exterior outer wall of a vessel 80. The exterior coating orlayer optionally can be a barrier coating or layer or layer, optionallyan oxygen barrier coating or layer or layer, or optionally a waterbarrier coating or layer or layer. The exterior coating or layer canalso be an armor layer that protects the outer wall of a vessel 80. Oneexample of a suitable exterior coating or layer can be polyvinylidenechloride, which functions both as a water barrier and an oxygen barrier.Optionally, the exterior coating or layer can be applied as awater-based coating or layer. The exterior coating or layer optionallycan be applied by dipping the vessel in it, spraying it on thepharmaceutical package or other vessel, or other expedients.

Yet another coating modality contemplated for protecting or passivatingan SiO_(x) barrier coating or layer can be coating the barrier coatingor layer using a polyamidoamine epichlorohydrin resin. For example, thebarrier coating or layer can be applied by dip coating in a fluidpolyamidoamine epichlorohydrin resin melt, solution or dispersion andcured by autoclaving or other heating at a temperature between 60 and100° C.

It is contemplated that a coating of polyamidoamine epichlorohydrinresin can be preferentially used in aqueous environments between pH 5-8,as such resins are known to provide high wet strength in paper in thatpH range. Wet strength is the ability to maintain mechanical strength ofpaper subjected to complete water soaking for extended periods of time,so it is contemplated that a coating of polyamidoamine epichlorohydrinresin on an SiO_(x) barrier coating or layer will have similarresistance to dissolution in aqueous media. It is also contemplatedthat, because polyamidoamine epichlorohydrin resin imparts a lubricityimprovement to paper, it will also provide lubricity in the form of acoating on a thermoplastic surface made of, for example, COC or COP.

Fluid Material

Optionally for any of the embodiments of FIGS. 7-8, the fluid material40 can have a pH between 5 and 6, optionally between 6 and 7, optionallybetween 7 and 8, optionally between 8 and 9, optionally between 6.5 and7.5, optionally between 7.5 and 8.5, optionally between 8.5 and 9.

Optionally for any of the embodiments of FIGS. 7-8, the fluid material40 can be a liquid at 20° C. and ambient pressure at sea level, which isdefined as a pressure of 760 mm Hg.

Optionally for any of the embodiments of FIGS. 7-8, the fluid material40 can be an aqueous liquid.

Optionally for any of the embodiments of FIGS. 7-8, the fluid material40 comprises a member or a combination of two or more members selectedfrom the group consisting of:

Inhalation Anesthetics

Aliflurane

Chloroform

Cyclopropane

Desflurane (Suprane)

Diethyl Ether

Enflurane (Ethrane)

Ethyl Chloride

Ethylene

Halothane (Fluothane)

Isoflurane (Forane, Isoflo)

Isopropenyl vinyl ether

Methoxyflurane

methoxyflurane,

Methoxypropane

Nitrous Oxide

Roflurane

Sevoflurane (Sevorane, Ultane, Sevoflo)

Teflurane

Trichloroethylene

Vinyl Ether

Xenon

Injectable Drugs

Ablavar (Gadofosveset Trisodium Injection)

Abarelix Depot

Abobotulinumtoxin A Injection (Dysport)

ABT-263

ABT-869

ABX-EFG

Accretropin (Somatropin Injection)

Acetadote (Acetylcysteine Injection)

Acetazolamide Injection (Acetazolamide Injection)

Acetylcysteine Injection (Acetadote)

Actemra (Tocilizumab Injection)

Acthrel (Corticorelin Ovine Triflutate for Injection)

Actummune

Activase

Acyclovir for Injection (Zovirax Injection)

Adacel

Adalimumab

Adenoscan (Adenosine Injection)

Adenosine Injection (Adenoscan)

Adrenaclick

AdreView (lobenguane I 123 Injection for Intravenous Use)

Afluria

Ak-Fluor (Fluorescein Injection)

Aldurazyme (Laronidase)

Alglucerase Injection (Ceredase)

Alkeran Injection (Melphalan Hcl Injection)

Allopurinol Sodium for Injection (Aloprim)

Aloprim (Allopurinol Sodium for Injection)

Alprostadil

Alsuma (Sumatriptan Injection)

ALTU-238

Amino Acid Injections

Aminosyn

Apidra

Apremilast

Alprostadil Dual Chamber System for Injection (Caverject Impulse)

AMG 009

AMG 076

AMG 102

AMG 108

AMG 114

AMG 162

AMG 220

AMG 221

AMG 222

AMG 223

AMG 317

AMG 379

AMG 386

AMG 403

AMG 477

AMG 479

AMG 517

AMG 531

AMG 557

AMG 623

AMG 655

AMG 706

AMG 714

AMG 745

AMG 785

AMG 811

AMG 827

AMG 837

AMG 853

AMG 951

Amiodarone HCl Injection (Amiodarone HCl Injection)

Amobarbital Sodium Injection (Amytal Sodium)

Amytal Sodium (Amobarbital Sodium Injection)

Anakinra

Anti-Abeta

Anti-Beta7

Anti-Beta20

Anti-CD4

Anti-CD20

Anti-CD40

Anti-IFNalpha

Anti-IL13

Anti-OX40L

Anti-oxLDS

Anti-NGF

Anti-NRP1

Arixtra

Amphadase (Hyaluronidase Inj)

Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection)

Anaprox

Anzemet Injection (Dolasetron Mesylate Injection)

Apidra (Insulin Glulisine [rDNA origin] Inj)

Apomab

Aranesp (darbepoetin alfa)

Argatroban (Argatroban Injection)

Arginine Hydrochloride Injection (R-Gene 10

Aristocort

Aristospan

Arsenic Trioxide Injection (Trisenox)

Articane HCl and Epinephrine Injection (Septocaine)

Arzerra (Ofatumumab Injection)

Asclera (Polidocanol Injection)

Ataluren

Ataluren-DMD

Atenolol Inj (Tenormin I.V. Injection)

Atracurium Besylate Injection (Atracurium Besylate Injection)

Avastin

Azactam Injection (Aztreonam Injection)

Azithromycin (Zithromax Injection)

Aztreonam Injection (Azactam Injection)

Baclofen Injection (Lioresal Intrathecal)

Bacteriostatic Water (Bacteriostatic Water for Injection)

Baclofen Injection (Lioresal Intrathecal)

Bal in Oil Ampules (Dimercarprol Injection)

BayHepB

BayTet

Benadryl

Bendamustine Hydrochloride Injection (Treanda)

Benztropine Mesylate Injection (Cogentin)

Betamethasone Injectable Suspension (Celestone Soluspan)

Bexxar

Bicillin C-R 900/300 (Penicillin G Benzathine and Penicillin G ProcaineInjection)

Blenoxane (Bleomycin Sulfate Injection)

Bleomycin Sulfate Injection (Blenoxane)

Boniva Injection (Ibandronate Sodium Injection)

Botox Cosmetic (OnabotulinumtoxinA for Injection)

BR3-FC

Bravelle (Urofollitropin Injection)

Bretylium (Bretylium Tosylate Injection)

Brevital Sodium (Methohexital Sodium for Injection)

Brethine

Briobacept

BTT-1023

Bupivacaine HCl

Byetta

Ca-DTPA (Pentetate Calcium Trisodium Inj)

Cabazitaxel Injection (Jevtana)

Caffeine Alkaloid (Caffeine and Sodium Benzoate Injection)

Calcijex Injection (Calcitrol)

Calcitrol (Calcijex Injection)

Calcium Chloride (Calcium Chloride Injection 10%)

Calcium Disodium Versenate (Edetate Calcium Disodium Injection)

Campath (Altemtuzumab)

Camptosar Injection (Irinotecan Hydrochloride)

Canakinumab Injection (Ilaris)

Capastat Sulfate (Capreomycin for Injection)

Capreomycin for Injection (Capastat Sulfate)

Cardiolite (Prep kit for Technetium Tc99 Sestamibi for Injection)

Carticel

Cathflo

Cefazolin and Dextrose for Injection (Cefazolin Injection)

Cefepime Hydrochloride

Cefotaxime

Ceftriaxone

Cerezyme

Carnitor Injection

Caverject

Celestone Soluspan

Celsior

Cerebyx (Fosphenytoin Sodium Injection)

Ceredase (Alglucerase Injection)

Ceretec (Technetium Tc99m Exametazime Injection)

Certolizumab

CF-101

Chloramphenicol Sodium Succinate (Chloramphenicol Sodium SuccinateInjection)

Chloramphenicol Sodium Succinate Injection (Chloramphenicol SodiumSuccinate)

Cholestagel (Colesevelam HCL)

Choriogonadotropin Alfa Injection (Ovidrel)

Cimzia

Cisplatin (Cisplatin Injection)

Clolar (Clofarabine Injection)

Clomiphine Citrate

Clonidine Injection (Duraclon)

Cogentin (Benztropine Mesylate Injection)

Colistimethate Injection (Coly-Mycin M)

Coly-Mycin M (Colistimethate Injection)

Compath

Conivaptan Hcl Injection (Vaprisol)

Conjugated Estrogens for Injection (Premarin Injection)

Copaxone

Corticorelin Ovine Triflutate for Injection (Acthrel)

Corvert (Ibutilide Fumarate Injection)

Cubicin (Daptomycin Injection)

CF-101

Cyanokit (Hydroxocobalamin for Injection)

Cytarabine Liposome Injection (DepoCyt)

Cyanocobalamin

Cytovene (ganciclovir)

D.H.E. 45

Dacetuzumab

Dacogen (Decitabine Injection)

Dalteparin

Dantrium IV (Dantrolene Sodium for Injection)

Dantrolene Sodium for Injection (Dantrium IV)

Daptomycin Injection (Cubicin)

Darbepoietin Alfa

DDAVP Injection (Desmopressin Acetate Injection)

Decavax

Decitabine Injection (Dacogen)

Dehydrated Alcohol (Dehydrated Alcohol Injection)

Denosumab Injection (Prolia)

Delatestryl

Delestrogen

Delteparin Sodium

Depacon (Valproate Sodium Injection)

Depo Medrol (Methylprednisolone Acetate Injectable Suspension)

DepoCyt (Cytarabine Liposome Injection)

DepoDur (Morphine Sulfate XR Liposome Injection)

Desmopressin Acetate Injection (DDAVP Injection)

Depo-Estradiol

Depo-Provera 104 mg/ml

Depo-Provera 150 mg/ml

Depo-Testosterone

Dexrazoxane for Injection, Intravenous Infusion Only (Totect)

Dextrose/Electrolytes

Dextrose and Sodium Chloride Inj (Dextrose 5% in 0.9% Sodium Chloride)

Dextrose

Diazepam Injection (Diazepam Injection)

Digoxin Injection (Lanoxin Injection)

Dilaudid-HP (Hydromorphone Hydrochloride Injection)

Dimercarprol Injection (Bal in Oil Ampules)

Diphenhydramine Injection (Benadryl Injection)

Dipyridamole Injection (Dipyridamole Injection)

DMOAD

Docetaxel for Injection (Taxotere)

Dolasetron Mesylate Injection (Anzemet Injection)

Doribax (Doripenem for Injection)

Doripenem for Injection (Doribax)

Doxercalciferol Injection (Hectorol Injection)

Doxil (Doxorubicin Hcl Liposome Injection)

Doxorubicin Hcl Liposome Injection (Doxil)

Duraclon (Clonidine Injection)

Duramorph (Morphine Injection)

Dysport (Abobotulinumtoxin A Injection)

Ecallantide Injection (Kalbitor)

EC-Naprosyn (naproxen)

Edetate Calcium Disodium Injection (Calcium Disodium Versenate)

Edex (Alprostadil for Injection)

Engerix

Edrophonium Injection (Enlon)

Eliglustat Tartate

Eloxatin (Oxaliplatin Injection)

Emend Injection (Fosaprepitant Dimeglumine Injection)

Enalaprilat Injection (Enalaprilat Injection)

Enlon (Edrophonium Injection)

Enoxaparin Sodium Injection (Lovenox)

Eovist (Gadoxetate Disodium Injection)

Enbrel (etanercept)

Enoxaparin

Epicel

Epinepherine

Epipen

Epipen Jr.

Epratuzumab

Erbitux

Ertapenem Injection (Invanz)

Erythropoieten

Essential Amino Acid Injection (Nephramine)

Estradiol Cypionate

Estradiol Valerate

Etanercept

Exenatide Injection (Byetta)

Evlotra

Fabrazyme (Adalsidase beta)

Famotidine Injection

FDG (Fludeoxyglucose F 18 Injection)

Feraheme (Ferumoxytol Injection)

Feridex I.V. (Ferumoxides Injectable Solution)

Fertinex

Ferumoxides Injectable Solution (Feridex I.V.)

Ferumoxytol Injection (Feraheme)

Flagyl Injection (Metronidazole Injection)

Fluarix

Fludara (Fludarabine Phosphate)

Fludeoxyglucose F 18 Injection (FDG)

Fluorescein Injection (Ak-Fluor)

Follistim AQ Cartridge (Follitropin Beta Injection)

Follitropin Alfa Injection (Gonal-f RFF)

Follitropin Beta Injection (Follistim AQ Cartridge)

Folotyn (Pralatrexate Solution for Intravenous Injection)

Fondaparinux

Forteo (Teriparatide (rDNA origin) Injection)

Fostamatinib

Fosaprepitant Dimeglumine Injection (Emend Injection)

Foscarnet Sodium Injection (Foscavir)

Foscavir (Foscarnet Sodium Injection)

Fosphenytoin Sodium Injection (Cerebyx)

Fospropofol Disodium Injection (Lusedra)

Fragmin

Fuzeon (enfuvirtide)

GA101

Gadobenate Dimeglumine Injection (Multihance)

Gadofosveset Trisodium Injection (Ablavar)

Gadoteridol Injection Solution (ProHance)

Gadoversetamide Injection (OptiMARK)

Gadoxetate Disodium Injection (Eovist)

Ganirelix (Ganirelix Acetate Injection)

Gardasil

GC1008

GDFD

Gemtuzumab Ozogamicin for Injection (Mylotarg)

Genotropin

Gentamicin Injection

GENZ-112638

Golimumab Injection (Simponi Injection)

Gonal-f RFF (Follitropin Alfa Injection)

Granisetron Hydrochloride (Kytril Injection)

Gentamicin Sulfate

Glatiramer Acetate

Glucagen

Glucagon

HAE1

Haldol (Haloperidol Injection)

Havrix

Hectorol Injection (Doxercalciferol Injection)

Hedgehog Pathway Inhibitor

Heparin

Herceptin

hG-CSF

Humalog

Human Growth Hormone

Humatrope

HuMax

Humegon

Humira

Humulin

Ibandronate Sodium Injection (Boniva Injection)

Ibuprofen Lysine Injection (NeoProfen)

Ibutilide Fumarate Injection (Corvert)

Idamycin PFS (Idarubicin Hydrochloride Injection)

Idarubicin Hydrochloride Injection (Idamycin PFS)

Ilaris (Canakinumab Injection)

Imipenem and Cilastatin for Injection (Primaxin I.V.)

Imitrex

Incobotulinumtoxin A for Injection (Xeomin)

Increlex (Mecasermin [rDNA origin] Injection)

Indocin IV (Indomethacin Inj)

Indomethacin Inj (Indocin IV)

Infanrix

Innohep

Insulin

Insulin Aspart [rDNA origin] Inj (NovoLog)

Insulin Glargine [rDNA origin] Injection (Lantus)

Insulin Glulisine [rDNA origin] Inj (Apidra)

Interferon alfa-2b, Recombinant for Injection (Intron A)

Intron A (Interferon alfa-2b, Recombinant for Injection)

Invanz (Ertapenem Injection)

Invega Sustenna (Paliperidone Palmitate Extended-Release InjectableSuspension)

Invirase (saquinavir mesylate)

lobenguane I 123 Injection for Intravenous Use (AdreView)

lopromide Injection (Ultravist)

loversol Injection (Optiray Injection)

Iplex (Mecasermin Rinfabate [rDNA origin] Injection)

Iprivask

Irinotecan Hydrochloride (Camptosar Injection)

Iron Sucrose Injection (Venofer)

Istodax (Romidepsin for Injection)

Itraconazole Injection (Sporanox Injection)

Jevtana (Cabazitaxel Injection)

Jonexa

Kalbitor (Ecallantide Injection)

KCL in D5NS (Potassium Chloride in 5% Dextrose and Sodium ChlorideInjection)

KCL in D5W

KCL in NS

Kenalog 10 Injection (Triamcinolone Acetonide Injectable Suspension)

Kepivance (Palifermin)

Keppra Injection (Levetiracetam)

Keratinocyte

KFG

Kinase Inhibitor

Kineret (Anakinra)

Kinlytic (Urokinase Injection)

Kinrix

Klonopin (clonazepam)

Kytril Injection (Granisetron Hydrochloride)

lacosamide Tablet and Injection (Vimpat)

Lactated Ringer's

Lanoxin Injection (Digoxin Injection)

Lansoprazole for Injection (Prevacid I.V.)

Lantus

Leucovorin Calcium (Leucovorin Calcium Injection)

Lente (L)

Leptin

Levemir

Leukine Sargramostim

Leuprolide Acetate

Levothyroxine

Levetiracetam (Keppra Injection)

Lovenox

Levocarnitine Injection (Carnitor Injection)

Lexiscan (Regadenoson Injection)

Lioresal Intrathecal (Baclofen Injection)

Liraglutide [rDNA] Injection (Victoza)

Lovenox (Enoxaparin Sodium Injection)

Lucentis (Ranibizumab Injection)

Lumizyme

Lupron (Leuprolide Acetate Injection)

Lusedra (Fospropofol Disodium Injection)

Maci

Magnesium Sulfate (Magnesium Sulfate Injection)

Mannitol Injection (Mannitol IV)

Marcaine (Bupivacaine Hydrochloride and Epinephrine Injection)

Maxipime (Cefepime Hydrochloride for Injection)

MDP Multidose Kit of Technetium Injection (Technetium Tc99m MedronateInjection)

Mecasermin [rDNA origin] Injection (Increlex)

Mecasermin Rinfabate [rDNA origin] Injection (Iplex)

Melphalan Hcl Injection (Alkeran Injection)

Methotrexate

Menactra

Menopur (Menotropins Injection)

Menotropins for Injection (Repronex)

Methohexital Sodium for Injection (Brevital Sodium)

Methyldopate Hydrochloride Injection, Solution (Methyldopate Hcl)

Methylene Blue (Methylene Blue Injection)

Methylprednisolone Acetate Injectable Suspension (Depo Medrol)

MetMab

Metoclopramide Injection (Reglan Injection)

Metrodin (Urofollitropin for Injection)

Metronidazole Injection (Flagyl Injection)

Miacalcin

Midazolam (Midazolam Injection)

Mimpara (Cinacalet)

Minocin Injection (Minocycline Inj)

Minocycline Inj (Minocin Injection)

Mipomersen

Mitoxantrone for Injection Concentrate (Novantrone)

Morphine Injection (Duramorph)

Morphine Sulfate XR Liposome Injection (DepoDur)

Morrhuate Sodium (Morrhuate Sodium Injection)

Motesanib

Mozobil (Plerixafor Injection)

Multihance (Gadobenate Dimeglumine Injection)

Multiple Electrolytes and Dextrose Injection

Multiple Electrolytes Injection

Mylotarg (Gemtuzumab Ozogamicin for Injection)

Myozyme (Alglucosidase alfa)

Nafcillin Injection (Nafcillin Sodium)

Nafcillin Sodium (Nafcillin Injection)

Naltrexone XR Inj (Vivitrol)

Naprosyn (naproxen)

NeoProfen (Ibuprofen Lysine Injection)

Nandrol Decanoate

Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection)

NEO-GAA

NeoTect (Technetium Tc 99m Depreotide Injection)

Nephramine (Essential Amino Acid Injection)

Neulasta (pegfilgrastim)

Neupogen (Filgrastim)

Novolin

Novolog

NeoRecormon

Neutrexin (Trimetrexate Glucuronate Inj)

NPH (N)

Nexterone (Amiodarone HCl Injection)

Norditropin (Somatropin Injection)

Normal Saline (Sodium Chloride Injection)

Novantrone (Mitoxantrone for Injection Concentrate)

Novolin 70/30 Innolet (70% NPH, Human Insulin Isophane Suspension and30%

Regular, Human Insulin Injection)

NovoLog (Insulin Aspart [rDNA origin] Inj)

Nplate (romiplostim)

Nutropin (Somatropin (rDNA origin) for Inj)

Nutropin AQ

Nutropin Depot (Somatropin (rDNA origin) for Inj)

Octreotide Acetate Injection (Sandostatin LAR)

Ocrelizumab

Ofatumumab Injection (Arzerra)

Olanzapine Extended Release Injectable Suspension (Zyprexa Relprevv)

Omnitarg

Omnitrope (Somatropin [rDNA origin] Injection)

Ondansetron Hydrochloride Injection (Zofran Injection)

OptiMARK (Gadoversetamide Injection)

Optiray Injection (loversol Injection)

Orencia

Osmitrol Injection in Aviva (Mannitol Injection in Aviva PlasticPharmaceutical package 210)

Osmitrol Injection in Viaflex (Mannitol Injection in Viaflex PlasticPharmaceutical

package 210)

Osteoprotegrin

Ovidrel (Choriogonadotropin Alfa Injection)

Oxacillin (Oxacillin for Injection)

Oxaliplatin Injection (Eloxatin)

Oxytocin Injection (Pitocin)

Paliperidone Palmitate Extended-Release Injectable Suspension (InvegaSustenna)

Pamidronate Disodium Injection (Pamidronate Disodium Injection)

Panitumumab Injection for Intravenous Use (Vectibix)

Papaverine Hydrochloride Injection (Papaverine Injection)

Papaverine Injection (Papaverine Hydrochloride Injection)

Parathyroid Hormone

Paricalcitol Injection Fliptop Vial (Zemplar Injection)

PARP Inhibitor

Pediarix

PEGIntron

Peginterferon

Pegfilgrastim

Penicillin G Benzathine and Penicillin G Procaine

Pentetate Calcium Trisodium Inj (Ca-DTPA)

Pentetate Zinc Trisodium Injection (Zn-DTPA)

Pepcid Injection (Famotidine Injection)

Pergonal

Pertuzumab

Phentolamine Mesylate (Phentolamine Mesylate for Injection)

Physostigmine Salicylate (Physostigmine Salicylate (injection))

Physostigmine Salicylate (injection) (Physostigmine Salicylate)

Piperacillin and Tazobactam Injection (Zosyn)

Pitocin (Oxytocin Injection)

Plasma-Lyte 148 (Multiple Electrolytes Inj)

Plasma-Lyte 56 and Dextrose (Multiple Electrolytes and DextroseInjection in Viaflex

Plastic Pharmaceutical package 210)

PlasmaLyte

Plerixafor Injection (Mozobil)

Polidocanol Injection (Asclera)

Potassium Chloride

Pralatrexate Solution for Intravenous Injection (Folotyn)

Pramlintide Acetate Injection (Symlin)

Premarin Injection (Conjugated Estrogens for Injection)

Prep kit for Technetium Tc99 Sestamibi for Injection (Cardiolite)

Prevacid I.V. (Lansoprazole for Injection)

Primaxin I.V. (Imipenem and Cilastatin for Injection)

Prochymal

Procrit

Progesterone

ProHance (Gadoteridol Injection Solution)

Prolia (Denosumab Injection)

Promethazine HCl Injection (Promethazine Hydrochloride Injection)

Propranolol Hydrochloride Injection (Propranolol HydrochlorideInjection)

Quinidine Gluconate Injection (Quinidine Injection)

Quinidine Injection (Quinidine Gluconate Injection)

R-Gene 10 (Arginine Hydrochloride Injection)

Ranibizumab Injection (Lucentis)

Ranitidine Hydrochloride Injection (Zantac Injection)

Raptiva

Reclast (Zoledronic Acid Injection)

Recombivarix HB

Regadenoson Injection (Lexiscan)

Reglan Injection (Metoclopramide Injection)

Remicade

Renagel

Renvela (Sevelamer Carbonate)

Repronex (Menotropins for Injection)

Retrovir IV (Zidovudine Injection)

rhApo2L/TRAIL

Ringer's and 5% Dextrose Injection (Ringers in Dextrose)

Ringer's Injection (Ringers Injection)

Rituxan

Rituximab

Rocephin (ceftriaxone)

Rocuronium Bromide Injection (Zemuron)

Roferon-A (interferon alfa-2a)

Romazicon (flumazenil)

Romidepsin for Injection (Istodax)

Saizen (Somatropin Injection)

Sandostatin LAR (Octreotide Acetate Injection)

Sclerostin Ab

Sensipar (cinacalcet)

Sensorcaine (Bupivacaine HCl Injections)

Septocaine (Articane HCl and Epinephrine Injection)

Serostim LQ (Somatropin (rDNA origin) Injection)

Simponi Injection (Golimumab Injection)

Sodium Acetate (Sodium Acetate Injection)

Sodium Bicarbonate (Sodium Bicarbonate 5% Injection)

Sodium Lactate (Sodium Lactate Injection in AVIVA)

Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)

Somatropin (rDNA origin) for Inj (Nutropin)

Sporanox Injection (Itraconazole Injection)

Stelara Injection (Ustekinumab)

Stemgen

Sufenta (Sufentanil Citrate Injection)

Sufentanil Citrate Injection (Sufenta)

Sumavel

Sumatriptan Injection (Alsuma)

Symlin

Symlin Pen

Systemic Hedgehog Antagonist

Synvisc-One (Hylan G-F 20 Single Intra-articular Injection)

Tarceva

Taxotere (Docetaxel for Injection)

Technetium Tc 99m

Telavancin for Injection (Vibativ)

Temsirolimus Injection (Torisel)

Tenormin I.V. Injection (Atenolol Inj)

Teriparatide (rDNA origin) Injection (Forteo)

Testosterone Cypionate

Testosterone Enanthate

Testosterone Propionate

Tev-Tropin (Somatropin, rDNA Origin, for Injection)

tgAAC94

Thallous Chloride

Theophylline

Thiotepa (Thiotepa Injection)

Thymoglobulin (Anti-Thymocyte Globulin (Rabbit)

Thyrogen (Thyrotropin Alfa for Injection)

Ticarcillin Disodium and Clavulanate Potassium Galaxy (TimentinInjection)

Tigan Injection (Trimethobenzamide Hydrochloride Injectable)

Timentin Injection (Ticarcillin Disodium and Clavulanate PotassiumGalaxy)

TNKase

Tobramycin Injection (Tobramycin Injection)

Tocilizumab Injection (Actemra)

Torisel (Temsirolimus Injection)

Totect (Dexrazoxane for Injection, Intravenous Infusion Only)

Trastuzumab-DM1

Travasol (Amino Acids (Injection))

Treanda (Bendamustine Hydrochloride Injection)

Trelstar (Triptorelin Pamoate for Injectable Suspension)

Triamcinolone Acetonide

Triamcinolone Diacetate

Triamcinolone Hexacetonide Injectable Suspension (Aristospan Injection20 mg)

Triesence (Triamcinolone Acetonide Injectable Suspension)

Trimethobenzamide Hydrochloride Injectable (Tigan Injection)

Trimetrexate Glucuronate Inj (Neutrexin)

Triptorelin Pamoate for Injectable Suspension (Trelstar)

Twinject

Trivaris (Triamcinolone Acetonide Injectable Suspension)

Trisenox (Arsenic Trioxide Injection)

Twinrix

Typhoid Vi

Ultravist (lopromide Injection)

Urofollitropin for Injection (Metrodin)

Urokinase Injection (Kinlytic)

Ustekinumab (Stelara Injection)

Ultralente (U)

Valium (diazepam)

Valproate Sodium Injection (Depacon)

Valtropin (Somatropin Injection)

Vancomycin Hydrochloride (Vancomycin Hydrochloride Injection)

Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride)

Vaprisol (Conivaptan Hcl Injection)

VAQTA

Vasovist (Gadofosveset Trisodium Injection for Intravenous Use)

Vectibix (Panitumumab Injection for Intravenous Use)

Venofer (Iron Sucrose Injection)

Verteporfin Inj (Visudyne)

Vibativ (Telavancin for Injection)

Victoza (Liraglutide [rDNA] Injection)

Vimpat (lacosamide Tablet and Injection)

Vinblastine Sulfate (Vinblastine Sulfate Injection)

Vincasar PFS (Vincristine Sulfate Injection)

Victoza

Vincristine Sulfate (Vincristine Sulfate Injection)

Visudyne (Verteporfin Inj)

Vitamin B-12

Vivitrol (Naltrexone XR Inj)

Voluven (Hydroxyethyl Starch in Sodium Chloride Injection)

Xeloda

Xenical (orlistat)

Xeomin (Incobotulinumtoxin A for Injection)

Xolair

Zantac Injection (Ranitidine Hydrochloride Injection)

Zemplar Injection (Paricalcitol Injection Fliptop Vial)

Zemuron (Rocuronium Bromide Injection)

Zenapax (daclizumab)

Zevalin

Zidovudine Injection (Retrovir IV)

Zithromax Injection (Azithromycin)

Zn-DTPA (Pentetate Zinc Trisodium Injection)

Zofran Injection (Ondansetron Hydrochloride Injection)

Zingo

Zoledronic Acid for Inj (Zometa)

Zoledronic Acid Injection (Reclast)

Zometa (Zoledronic Acid for Inj)

Zosyn (Piperacillin and Tazobactam Injection)

Zyprexa Relprevv (Olanzapine Extended Release Injectable Suspension)

Liquid Drugs (Non-Injectable)

Abilify

AccuNeb (Albuterol Sulfate Inhalation Solution)

Actidose Aqua (Activated Charcoal Suspension)

Activated Charcoal Suspension (Actidose Aqua)

Advair

Agenerase Oral Solution (Amprenavir Oral Solution)

Akten (Lidocaine Hydrochloride Ophthalmic Gel)

Alamast (Pemirolast Potassium Ophthalmic Solution)

Albumin (Human) 5% Solution (Buminate 5%)

Albuterol Sulfate Inhalation Solution

Alinia

Alocril

Alphagan

Alrex

Alvesco

Amprenavir Oral Solution

Analpram-HC

Arformoterol Tartrate Inhalation Solution (Brovana)

Aristospan Injection 20 mg (Triamcinolone Hexacetonide InjectableSuspension)

Asacol

Asmanex

Astepro

Astepro (Azelastine Hydrochloride Nasal Spray)

Atrovent Nasal Spray (Ipratropium Bromide Nasal Spray)

Atrovent Nasal Spray 0.06

Augmentin ES-600

Azasite (Azithromycin Ophthalmic Solution)

Azelaic Acid (Finacea Gel)

Azelastine Hydrochloride Nasal Spray (Astepro)

Azelex (Azelaic Acid Cream)

Azopt (Brinzolamide Ophthalmic Suspension)

Bacteriostatic Saline

Balanced Salt

Bepotastine

Bactroban Nasal

Bactroban

Beclovent

Benzac W

Betimol

Betoptic S

Bepreve

Bimatoprost Ophthalmic Solution

Bleph 10 (Sulfacetamide Sodium Ophthalmic Solution 10%)

Brinzolamide Ophthalmic Suspension (Azopt)

Bromfenac Ophthalmic Solution (Xibrom)

Bromhist

Brovana (Arformoterol Tartrate Inhalation Solution)

Budesonide Inhalation Suspension (Pulmicort Respules)

Cambia (Diclofenac Potassium for Oral Solution)

Capex

Carac

Carboxine-PSE

Carnitor

Cayston (Aztreonam for Inhalation Solution)

Cellcept

Centany

Cerumenex

Ciloxan Ophthalmic Solution (Ciprofloxacin HCL Ophthalmic Solution)

Ciprodex

Ciprofloxacin HCL Ophthalmic Solution (Ciloxan Ophthalmic Solution)

Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)

CoLyte (PEG Electrolytes Solution)

Combiven

Comtan

Condylox

Cordran

Cortisporin Ophthalmic Suspension

Cortisporin Otic Suspension

Cromolyn Sodium Inhalation Solution (Intal Nebulizer Solution)

Cromolyn Sodium Ophthalmic Solution (Opticrom)

Crystalline Amino Acid Solution with Electrolytes (AminosynElectrolytes)

Cutivate

Cuvposa (Glycopyrrolate Oral Solution)

Cyanocobalamin (CaloMist Nasal Spray)

Cyclosporine Oral Solution (Gengraf Oral Solution)

Cyclogyl

Cysview (Hexaminolevulinate Hydrochloride Intravesical Solution)

DermOtic Oil (Fluocinolone Acetonide Oil Ear Drops)

Desmopressin Acetate Nasal Spray

DDAVP

Derma-Smoothe/FS

Dexamethasone Intensol

Dianeal Low Calcium

Dianeal PD

Diclofenac Potassium for Oral Solution (Cambia)

Didanosine Pediatric Powder for Oral Solution (Videx)

Differin

Dilantin 125 (Phenytoin Oral Suspension)

Ditropan

Dorzolamide Hydrochloride Ophthalmic Solution (Trusopt)

Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution (Cosopt)

Dovonex Scalp (Calcipotriene Solution)

Doxycycline Calcium Oral Suspension (Vibramycin Oral)

Efudex

Elaprase (Idursulfase Solution)

Elestat (Epinastine HCl Ophthalmic Solution)

Elocon

Epinastine HCl Ophthalmic Solution (Elestat)

Epivir HBV

Epogen (Epoetin alfa)

Erythromycin Topical Solution 1.5% (Staticin)

Ethiodol (Ethiodized Oil)

Ethosuximide Oral Solution (Zarontin Oral Solution)

Eurax

Extraneal (Icodextrin Peritoneal Dialysis Solution)

Felbatol

Feridex I.V. (Ferumoxides Injectable Solution)

Flovent

Floxin Otic (Ofloxacin Otic Solution)

Flo-Pred (Prednisolone Acetate Oral Suspension)

Fluoroplex

Flunisolide Nasal Solution (Flunisolide Nasal Spray 0.025%)

Fluorometholone Ophthalmic Suspension (FML)

Flurbiprofen Sodium Ophthalmic Solution (Ocufen)

FML

Foradil

Formoterol Fumarate Inhalation Solution (Perforomist)

Fosamax

Furadantin (Nitrofurantoin Oral Suspension)

Furoxone

Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)

Gantrisin (Acetyl Sulfisoxazole Pediatric Suspension)

Gatifloxacin Ophthalmic Solution (Zymar)

Gengraf Oral Solution (Cyclosporine Oral Solution)

Glycopyrrolate Oral Solution (Cuvposa)

Halcinonide Topical Solution (Halog Solution)

Halog Solution (Halcinonide Topical Solution)

HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution)

Heparin Lock Flush Solution (Hepflush 10

Hexaminolevulinate Hydrochloride Intravesical Solution (Cysview)

Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab Elixir)

Hydroquinone 3% Topical Solution (Melquin-3 Topical Solution)

IAP Antagonist

Isopto

Ipratropium Bromide Nasal Spray (Atrovent Nasal Spray)

Itraconazole Oral Solution (Sporanox Oral Solution)

Ketorolac Tromethamine Ophthalmic Solution (Acular LS)

Kaletra

Lanoxin

Lexiva

Leuprolide Acetate for Depot Suspension (Lupron Depot 11.25 mg)

Levobetaxolol Hydrochloride Ophthalmic Suspension (Betaxon)

Levocarnitine Tablets, Oral Solution, Sugar-Free (Carnitor)

Levofloxacin Ophthalmic Solution 0.5% (Quixin)

Lidocaine HCl Sterile Solution (Xylocaine MPF Sterile Solution)

Lok Pak (Heparin Lock Flush Solution)

Lorazepam Intensol

Lortab Elixir (Hydrocodone Bitartrate and Acetaminophen Oral Solution)

Lotemax (Loteprednol Etabonate Ophthalmic Suspension)

Loteprednol Etabonate Ophthalmic Suspension (Alrex)

Low Calcium Peritoneal Dialysis Solutions (Dianeal Low Calcium)

Lumigan (Bimatoprost Ophthalmic Solution 0.03% for Glaucoma)

Lupron Depot 11.25 mg (Leuprolide Acetate for Depot Suspension)

Megestrol Acetate Oral Suspension (Megestrol Acetate Oral Suspension)

MEK Inhibitor

Mepron

Mesnex

Mestinon

Mesalamine Rectal Suspension Enema (Rowasa)

Melquin-3 Topical Solution (Hydroquinone 3% Topical Solution)

MetMab

Methyldopate Hcl (Methyldopate Hydrochloride Injection, Solution)

Methylin Oral Solution (Methylphenidate HCl Oral Solution 5 mg/5 mL and10 mg/5 mL)

Methylprednisolone Acetate Injectable Suspension (Depo Medrol)

Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5 mL (MethylinOral Solution)

Methylprednisolone sodium succinate (Solu Medrol)

Metipranolol Ophthalmic Solution (Optipranolol)

Migranal

Miochol-E (Acetylcholine Chloride Intraocular Solution)

Micro-K for Liquid Suspension (Potassium Chloride Extended ReleaseFormulation for Liquid Suspension)

Minocin (Minocycline Hydrochloride Oral Suspension)

Nasacort

Neomycin and Polymyxin B Sulfates and Hydrocortisone

Nepafenac Ophthalmic Suspension (Nevanac)

Nevanac (Nepafenac Ophthalmic Suspension)

Nitrofurantoin Oral Suspension (Furadantin)

Noxafil (Posaconazole Oral Suspension)

Nystatin (oral) (Nystatin Oral Suspension)

Nystatin Oral Suspension (Nystatin (oral))

Ocufen (Flurbiprofen Sodium Ophthalmic Solution)

Ofloxacin Ophthalmic Solution (Ofloxacin Ophthalmic Solution)

Ofloxacin Otic Solution (Floxin Otic)

Olopatadine Hydrochloride Ophthalmic Solution (Pataday)

Opticrom (Cromolyn Sodium Ophthalmic Solution)

Optipranolol (Metipranolol Ophthalmic Solution)

Patanol

Pediapred

PerioGard

Phenytoin Oral Suspension (Dilantin 125)

Phisohex

Posaconazole Oral Suspension (Noxafil)

Potassium Chloride Extended Release Formulation for Liquid Suspension(Micro-K for

Liquid Suspension)

Pataday (Olopatadine Hydrochloride Ophthalmic Solution)

Patanase Nasal Spray (Olopatadine Hydrochloride Nasal Spray)

PEG Electrolytes Solution (CoLyte)

Pemirolast Potassium Ophthalmic Solution (Alamast)

Penlac (Ciclopirox Topical Solution)

PENNSAID (Diclofenac Sodium Topical Solution)

Perforomist (Formoterol Fumarate Inhalation Solution)

Peritoneal Dialysis Solution

Phenylephrine Hydrochloride Ophthalmic Solution (Neo-Synephrine)

Phospholine Iodide (Echothiophate Iodide for Ophthalmic Solution)

Podofilox (Podofilox Topical Solution)

Pred Forte (Prednisolone Acetate Ophthalmic Suspension)

Pralatrexate Solution for Intravenous Injection (Folotyn)

Pred Mild

Prednisone Intensol

Prednisolone Acetate Ophthalmic Suspension (Pred Forte)

Prevacid

PrismaSol Solution (Sterile Hemofiltration Hemodiafiltration Solution)

ProAir

Proglycem

ProHance (Gadoteridol Injection Solution)

Proparacaine Hydrochloride Ophthalmic Solution (Alcaine)

Propine

Pulmicort

Pulmozyme

Quixin (Levofloxacin Ophthalmic Solution 0.5%)

QVAR

Rapamune

Rebetol

Relacon-HC

Rotarix (Rotavirus Vaccine, Live, Oral Suspension)

Rotavirus Vaccine, Live, Oral Suspension (Rotarix)

Rowasa (Mesalamine Rectal Suspension Enema)

Sabril (Vigabatrin Oral Solution)

Sacrosidase Oral Solution (Sucraid)

Sandimmune

Sepra

Serevent Diskus

Solu Cortef (Hydrocortisone Sodium Succinate)

Solu Medrol (Methylprednisolone sodium succinate)

Spiriva

Sporanox Oral Solution (Itraconazole Oral Solution)

Staticin (Erythromycin Topical Solution 1.5%)

Stalevo

Starlix

Sterile Hemofiltration Hemodiafiltration Solution (PrismaSol Solution)

Stimate

Sucralfate (Carafate Suspension)

Sulfacetamide Sodium Ophthalmic Solution 10% (Bleph 10

Synarel Nasal Solution (Nafarelin Acetate Nasal Solution forEndometriosis)

Taclonex Scalp (Calcipotriene and Betamethasone Dipropionate TopicalSuspension)

Tamiflu

Tobi

TobraDex

Tobradex ST (Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05%)

Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05% (Tobradex ST)

Timolol

Timoptic

Travatan Z

Treprostinil Inhalation Solution (Tyvaso)

Trusopt (Dorzolamide Hydrochloride Ophthalmic Solution)

Tyvaso (Treprostinil Inhalation Solution)

Ventolin

Vfend

Vibramycin Oral (Doxycycline Calcium Oral Suspension)

Videx (Didanosine Pediatric Powder for Oral Solution)

Vigabatrin Oral Solution (Sabril)

Viokase

Viracept

Viramune

Vitamin K1 (Fluid Colloidal Solution of Vitamin K1)

Voltaren Ophthalmic (Diclofenac Sodium Ophthalmic Solution)

Zarontin Oral Solution (Ethosuximide Oral Solution)

Ziagen

Zyvox

Zymar (Gatifloxacin Ophthalmic Solution)

Zymaxid (Gatifloxacin Ophthalmic Solution)

Drug Classes

5-alpha-reductase inhibitors

5-aminosalicylates

5HT3 receptor antagonists

adamantane antivirals

adrenal cortical steroids

adrenal corticosteroid inhibitors

adrenergic bronchodilators

agents for hypertensive emergencies

agents for pulmonary hypertension

aldosterone receptor antagonists

alkylating agents

alpha-adrenoreceptor antagonists

alpha-glucosidase inhibitors

alternative medicines

amebicides

aminoglycosides

aminopenicillins

aminosalicylates

amylin analogs

Analgesic Combinations

Analgesics

androgens and anabolic steroids

angiotensin converting enzyme inhibitors

angiotensin II inhibitors

anorectal preparations

anorexiants

antacids

anthelmintics

anti-angiogenic ophthalmic agents

anti-CTLA-4 monoclonal antibodies

anti-infectives

antiadrenergic agents, centrally acting

antiadrenergic agents, peripherally acting

antiandrogens

antianginal agents

antiarrhythmic agents

antiasthmatic combinations

antibiotics/antineoplastics

anticholinergic antiemetics

anticholinergic antiparkinson agents

anticholinergic bronchodilators

anticholinergic chronotropic agents

anticholinergics/antispasmodics

anticoagulants

anticonvulsants

antidepressants

antidiabetic agents

antidiabetic combinations

antidiarrheals

antidiuretic hormones

antidotes

antiemetic/antivertigo agents

antifungals

antigonadotropic agents

antigout agents

antihistamines

antihyperlipidemic agents

antihyperlipidemic combinations

antihypertensive combinations

antihyperuricemic agents

antimalarial agents

antimalarial combinations

antimalarial quinolines

antimetabolites

antimigraine agents

antineoplastic detoxifying agents

antineoplastic interferons

antineoplastic monoclonal antibodies

antineoplastics

antiparkinson agents

antiplatelet agents

antipseudomonal penicillins

antipsoriatics

antipsychotics

antirheumatics

antiseptic and germicides

antithyroid agents

antitoxins and antivenins

antituberculosis agents

antituberculosis combinations

antitussives

antiviral agents

antiviral combinations

antiviral interferons

anxiolytics, sedatives, and hypnotics

aromatase inhibitors

atypical antipsychotics

azole antifungals

bacterial vaccines

barbiturate anticonvulsants

barbiturates

BCR-ABL tyrosine kinase inhibitors

benzodiazepine anticonvulsants

benzodiazepines

beta-adrenergic blocking agents

beta-lactamase inhibitors

bile acid sequestrants

biologicals

bisphosphonates

bone resorption inhibitors

bronchodilator combinations

bronchodilators

calcitonin

calcium channel blocking agents

carbamate anticonvulsants

carbapenems

carbonic anhydrase inhibitor anticonvulsants

carbonic anhydrase inhibitors

cardiac stressing agents

cardioselective beta blockers

cardiovascular agents

catecholamines

CD20 monoclonal antibodies

CD33 monoclonal antibodies

CD52 monoclonal antibodies

central nervous system agents

cephalosporins

cerumenolytics

chelating agents

chemokine receptor antagonist

chloride channel activators

cholesterol absorption inhibitors

cholinergic agonists

cholinergic muscle stimulants

cholinesterase inhibitors

CNS stimulants

coagulation modifiers

colony stimulating factors

contraceptives

corticotropin

coumarins and indandiones

cox-2 inhibitors

decongestants

dermatological agents

diagnostic radiopharmaceuticals

dibenzazepine anticonvulsants

digestive enzymes

dipeptidyl peptidase 4 inhibitors

diuretics

dopaminergic antiparkinsonism agents

drugs used in alcohol dependence

echinocandins

EGFR inhibitors

estrogen receptor antagonists

estrogens

expectorants

factor Xa inhibitors

fatty acid derivative anticonvulsants

fibric acid derivatives

first generation cephalosporins

fourth generation cephalosporins

functional bowel disorder agents

gallstone solubilizing agents

gamma-aminobutyric acid analogs

gamma-aminobutyric acid reuptake inhibitors

gamma-aminobutyric acid transaminase inhibitors

gastrointestinal agents

general anesthetics

genitourinary tract agents

GI stimulants

glucocorticoids

glucose elevating agents

glycopeptide antibiotics

glycoprotein platelet inhibitors

glycylcyclines

gonadotropin releasing hormones

gonadotropin-releasing hormone antagonists

gonadotropins

group I antiarrhythmics

group II antiarrhythmics

group III antiarrhythmics

group IV antiarrhythmics

group V antiarrhythmics

growth hormone receptor blockers

growth hormones

H. pylori eradication agents

H2 antagonists

hematopoietic stem cell mobilizer

heparin antagonists

heparins

HER2 inhibitors

herbal products

histone deacetylase inhibitors

hormone replacement therapy

hormones

hormones/antineoplastics

hydantoin anticonvulsants

illicit (street) drugs

immune globulins

immunologic agents

immunosuppressive agents

impotence agents

in vivo diagnostic biologicals

incretin mimetics

inhaled anti-infectives

inhaled corticosteroids

inotropic agents

insulin

insulin-like growth factor

integrase strand transfer inhibitor

interferons

intravenous nutritional products

iodinated contrast media

ionic iodinated contrast media

iron products

ketolides

laxatives

leprostatics

leukotriene modifiers

lincomycin derivatives

lipoglycopeptides

local injectable anesthetics

loop diuretics

lung surfactants

lymphatic staining agents

lysosomal enzymes

macrolide derivatives

macrolides

magnetic resonance imaging contrast media

mast cell stabilizers

medical gas

meglitinides

metabolic agents

methylxanthines

mineralocorticoids

minerals and electrolytes

miscellaneous agents

miscellaneous analgesics

miscellaneous antibiotics

miscellaneous anticonvulsants

miscellaneous antidepressants

miscellaneous antidiabetic agents

miscellaneous antiemetics

miscellaneous antifungals

miscellaneous antihyperlipidemic agents

miscellaneous antimalarials

miscellaneous antineoplastics

miscellaneous antiparkinson agents

miscellaneous antipsychotic agents

miscellaneous antituberculosis agents

miscellaneous antivirals

miscellaneous anxiolytics, sedatives and hypnotics

miscellaneous biologicals

miscellaneous bone resorption inhibitors

miscellaneous cardiovascular agents

miscellaneous central nervous system agents

miscellaneous coagulation modifiers

miscellaneous diuretics

miscellaneous genitourinary tract agents

miscellaneous GI agents

miscellaneous hormones

miscellaneous metabolic agents

miscellaneous ophthalmic agents

miscellaneous otic agents

miscellaneous respiratory agents

miscellaneous sex hormones

miscellaneous topical agents

miscellaneous uncategorized agents

miscellaneous vaginal agents

mitotic inhibitors

monoamine oxidase inhibitors

monoclonal antibodies

mouth and throat products

mTOR inhibitors

mTOR kinase inhibitors

mucolytics

multikinase inhibitors

muscle relaxants

mydriatics

narcotic analgesic combinations

narcotic analgesics

nasal anti-infectives

nasal antihistamines and decongestants

nasal lubricants and irrigations

nasal preparations

nasal steroids

natural penicillins

neuraminidase inhibitors

neuromuscular blocking agents

next generation cephalosporins

nicotinic acid derivatives

nitrates

NNRTIs

non-cardioselective beta blockers

non-iodinated contrast media

non-ionic iodinated contrast media

non-sulfonylureas

nonsteroidal anti-inflammatory agents

norepinephrine reuptake inhibitors

norepinephrine-dopamine reuptake inhibitors

nucleoside reverse transcriptase inhibitors (NRTIs)

nutraceutical products

nutritional products

ophthalmic anesthetics

ophthalmic anti-infectives

ophthalmic anti-inflammatory agents

ophthalmic antihistamines and decongestants

ophthalmic diagnostic agents

ophthalmic glaucoma agents

ophthalmic lubricants and irrigations

ophthalmic preparations

ophthalmic steroids

ophthalmic steroids with anti-infectives

ophthalmic surgical agents

oral nutritional supplements

otic anesthetics

otic anti-infectives

otic preparations

otic steroids

otic steroids with anti-infectives

oxazolidinedione anticonvulsants

parathyroid hormone and analogs

penicillinase resistant penicillins

penicillins

peripheral opioid receptor antagonists

peripheral vasodilators

peripherally acting antiobesity agents

phenothiazine antiemetics

phenothiazine antipsychotics

phenylpiperazine antidepressants

plasma expanders

platelet aggregation inhibitors

platelet-stimulating agents

polyenes

potassium-sparing diuretics

probiotics

progesterone receptor modulators

progestins

prolactin inhibitors

prostaglandin D2 antagonists

protease inhibitors

proton pump inhibitors

psoralens

psychotherapeutic agents

psychotherapeutic combinations

purine nucleosides

pyrrolidine anticonvulsants

quinolones

radiocontrast agents

radiologic adjuncts

radiologic agents

radiologic conjugating agents

radiopharmaceuticals

RANK ligand inhibitors

recombinant human erythropoietins

renin inhibitors

respiratory agents

respiratory inhalant products

rifamycin derivatives

salicylates

sclerosing agents

second generation cephalosporins

selective estrogen receptor modulators

selective serotonin reuptake inhibitors

serotonin-norepinephrine reuptake inhibitors

serotoninergic neuroenteric modulators

sex hormone combinations

sex hormones

skeletal muscle relaxant combinations

skeletal muscle relaxants

smoking cessation agents

somatostatin and somatostatin analogs

spermicides

statins

sterile irrigating solutions

streptomyces derivatives

succinimide anticonvulsants

sulfonamides

sulfonylureas

synthetic ovulation stimulants

tetracyclic antidepressants

tetracyclines

therapeutic radiopharmaceuticals

thiazide diuretics

thiazolidinediones

thioxanthenes

third generation cephalosporins

thrombin inhibitors

thrombolytics

thyroid drugs

tocolytic agents

topical acne agents

topical agents

topical anesthetics

topical anti-infectives

topical antibiotics

topical antifungals

topical antihistamines

topical antipsoriatics

topical antivirals

topical astringents

topical debriding agents

topical depigmenting agents

topical emollients

topical keratolytics

topical steroids

topical steroids with anti-infectives

toxoids

triazine anticonvulsants

tricyclic antidepressants

trifunctional monoclonal antibodies

tumor necrosis factor (TNF) inhibitors

tyrosine kinase inhibitors

ultrasound contrast media

upper respiratory combinations

urea anticonvulsants

urinary anti-infectives

urinary antispasmodics

urinary pH modifiers

uterotonic agents

vaccine

vaccine combinations

vaginal anti-infectives

vaginal preparations

vasodilators

vasopressin antagonists

vasopressors

VEGF/VEGFR inhibitors

viral vaccines

viscosupplementation agents

vitamin and mineral combinations

vitamins

Diagnostic Tests

17-Hydroxyprogesterone

ACE (Angiotensin I converting enzyme)

Acetaminophen

Acid phosphatase

ACTH

Activated clotting time

Activated protein C resistance

Adrenocorticotropic hormone (ACTH)

Alanine aminotransferase (ALT)

Albumin

Aldolase

Aldosterone

Alkaline phosphatase

Alkaline phosphatase (ALP)

Alpha1-antitrypsin

Alpha-fetoprotein

Alpha-fetoprotien

Ammonia levels

Amylase

ANA (antinuclear antibodies)

ANA (antinuclear antibodies)

Angiotensin-converting enzyme (ACE)

Anion gap

Anticardiolipin antibody

Anticardiolipin antibodies (ACA)

Anti-centromere antibody

Antidiuretic hormone

Anti-DNA

Anti-Dnase-B

Anti-Gliadin antibody

Anti-glomerular basement membrane antibody

Anti-HBc (Hepatitis B core antibodies

Anti-HBs (Hepatitis B surface antibody

Antiphospholipid antibody

Anti-RNA polymerase

Anti-Smith (Sm) antibodies

Anti-Smooth Muscle antibody

Antistreptolysin O (ASO)

Antithrombin III

Anti-Xa activity

Anti-Xa assay

Apolipoproteins

Arsenic

Aspartate aminotransferase (AST)

B12

Basophil

Beta-2-Microglobulin

Beta-hydroxybutyrate

B-HCG

Bilirubin

Bilirubin, direct

Bilirubin, indirect

Bilirubin, total

Bleeding time

Blood gases (arterial)

Blood urea nitrogen (BUN)

BUN

BUN (blood urea nitrogen)

CA 125

CA 15-3

CA 19-9

Calcitonin

Calcium

Calcium (ionized)

Carbon monoxide (CO)

Carcinoembryonic antigen (CEA)

CBC

CEA

CEA (carcinoembryonic antigen)

Ceruloplasmin

CH50Chloride

Cholesterol

Cholesterol, HDL

Clot lysis time

Clot retraction time

CMP

CO2

Cold agglutinins

Complement C3

Copper

Corticotrophin releasing hormone (CRH) stimulation test

Cortisol

Cortrosyn stimulation test

C-peptide

CPK (Total)

CPK-MB

C-reactive protein

Creatinine

Creatinine kinase (CK)

Cryoglobulins

DAT (Direct antiglobulin test)

D-Dimer

Dexamethasone suppression test

DHEA-S

Dilute Russell viper venom

Elliptocytes

Eosinophil

Erythrocyte sedimentation rate (ESR)

Estradiol

Estriol

Ethanol

Ethylene glycol

Euglobulin lysis

Factor V Leiden

Factor VIII inhibitor

Factor VIII level

Ferritin

Fibrin split products

Fibrinogen

Folate

Folate (serum

Fractional excretion of sodium (FENA)

FSH (follicle stimulating factor)

FTA-ABS

Gamma glutamyl transferase (GGT)

Gastrin

GGTP (Gamma glutamyl transferase)

Glucose

Growth hormone

Haptoglobin

HBeAg (Hepatitis Be antigen)

HBs-Ag (Hepatitis B surface antigen)

Helicobacter pylori

Hematocrit

Hematocrit (HCT)

Hemoglobin

Hemoglobin A1C

Hemoglobin electrophoresis

Hepatitis A antibodies

Hepatitis C antibodies

IAT (Indirect antiglobulin test)

Immunofixation (IFE)

Iron

Lactate dehydrogenase (LDH)

Lactic acid (lactate)

LDH

LH (Leutinizing hormone

Lipase

Lupus anticoagulant

Lymphocyte

Magnesium

MCH (mean corpuscular hemoglobin

MCHC (mean corpuscular hemoglobin concentration)

MCV (mean corpuscular volume)

Methylmalonate

Monocyte

MPV (mean platelet volume)

Myoglobin

Neutrophil

Parathyroid hormone (PTH)

Phosphorus

Platelets (pit)

Potassium

Prealbumin

Prolactin

Prostate specific antigen (PSA)

Protein C

Protein S

PSA (prostate specific antigen)

PT (Prothrombin time)

PTT (Partial thromboplastin time)

RDW (red cell distribution width)

Renin

Rennin

Reticulocyte count

reticulocytes

Rheumatoid factor (RF)

Sed Rate

Serum glutamic-pyruvic transaminase (SGPT

Serum protein electrophoresis (SPEP)

Sodium

T3-resin uptake (T3RU)

T4, Free

Thrombin time

Thyroid stimulating hormone (TSH)

Thyroxine (T4

Total iron binding capacity (TIBC)

Total protein

Transferrin

Transferrin saturation

Triglyceride (TG)

Troponin

Uric acid

Vitamin B12

White blood cells (WBC)

Widal test

As several examples, the fluid material 40 can be an inhalationanesthetic, a drug, or a diagnostic test material. Any of these fluidmaterials 40 can be an injectable material, a volatile material capableof being inhaled, or otherwise capable of being introduced into asubject.

Other Uses of the Passivation Layer or pH Protective Coating

A vessel with a passivation layer or pH protective coating as describedherein can also be evacuated and stored in an evacuated state. Forexample, the passivation layer or pH protective coating allows bettermaintenance of the vacuum in comparison to a corresponding vesselwithout a passivation layer or pH protective coating. In one aspect ofthis embodiment, the vessel with a passivation layer or pH protectivecoating can be a blood collection tube. The tube can also contain anagent for preventing blood clotting or platelet activation, for exampleEDTA or heparin.

Even another embodiment can be a medical or diagnostic kit including avessel having a passivation layer or pH protective coating as defined inany embodiment herein on a substrate as defined in any embodimentherein. Optionally, the kit additionally includes a medicament ordiagnostic agent as defined in any embodiment herein which is containedin the vessel with a passivation layer or pH protective coating incontact with the coating or layer; and/or a hypodermic needle,double-ended needle, or other delivery conduit; and/or an instructionsheet.

Use of the passivation layer or pH protective coating according to anydescribed embodiment is contemplated for preventing or reducingprecipitation and/or clotting or platelet activation of a compound or acomponent of the composition in contact with the coating or layer.

The use of a coated substrate according to any described embodiment iscontemplated for storing insulin. As one option, precipitation of theinsulin can be prevented or reduced by providing vessel to contain theinsulin having a contact surface including a passivation layer or pHprotective coating.

As another option, the compound or a component of the composition can beblood or a blood fraction, and blood clotting or platelet activation canbe prevented or reduced by storing the blood in the blood collectiontube in contact with a passivation layer or pH protective coating.Optionally, the blood collection tube can contain an agent forpreventing blood clotting or platelet activation, for exampleethylenediamineteetraacetic acid (EDTA), a sodium salt thereof, orheparin. The blood collection tube can include a passivation layer or pHprotective coating for preventing the agent from attacking an SiO_(x)barrier coating or layer in the vessel. The use of a coated substrateaccording to any described embodiment is contemplated for storing blood.Optionally, the stored blood can be viable for return to the vascularsystem of a patient.

Use of a coating or layer according to any described embodiment can becontemplated as (i) a lubricity coating having a lower frictionalresistance than the uncoated surface; and/or (ii) a passivation layer orpH protective coating preventing dissolution of the barrier coating orlayer in contact with a fluid, and/or (iii) a hydrophobic layer that canbe more hydrophobic than the uncoated surface.

Measurement of Coating Thickness

The thickness of a PECVD coating or layer such as the passivation layeror pH protective coating, the barrier coating or layer, the lubricitycoating or layer, and/or a composite of any two or more of these layerscan be measured, for example, by transmission electron microscopy (TEM).An exemplary TEM image for a lubricity and/or passivation layer or pHprotective coating on an SiO_(x) barrier coating or layer is shown inFIG. 11. An exemplary TEM image for an SiO_(x) barrier coating or layeron a substrate is shown in FIG. 12.

The TEM can be carried out, for example, as follows. Samples can beprepared for Focused Ion Beam (FIB) cross-sectioning in two ways. Eitherthe samples can be first coated with a thin layer of carbon (50-100 nmthick) and then coated with a sputtered coating or layer of platinum(50-100 nm thick) using a K575X Emitech passivation layer or pHprotective coating system, or the samples can be coated directly withthe protective sputtered Pt layer. The coated samples can be placed inan FEI FIB200 FIB system. An additional coating or layer of platinum canbe FIB-deposited by injection of an organometallic gas while rasteringthe 30 kV gallium ion beam over the area of interest. The area ofinterest for each sample can be chosen to be a location half way downthe length of the syringe barrel. Thin cross sections measuringapproximately 15 μm (“micrometers”) long, 2 μm wide and 15 μm deep canbe extracted from the die surface using an in-situ FIB lift-outtechnique. The cross sections can be attached to a 200 mesh copper TEMgrid using FIB-deposited platinum. One or two windows in each section,measuring about 8 μm wide, can be thinned to electron transparency usingthe gallium ion beam of the FEI FIB.

Cross-sectional image analysis of the prepared samples can be performedutilizing either a Transmission Electron Microscope (TEM), or a ScanningTransmission Electron Microscope (STEM), or both. All imaging data canbe recorded digitally. For STEM imaging, the grid with the thinned foilscan be transferred to a Hitachi HD2300 dedicated STEM. Scanningtransmitted electron images can be acquired at appropriatemagnifications in atomic number contrast mode (ZC) and transmittedelectron mode (TE). The following instrument settings can be used.

Scanning Transmission Electron Instrument Microscope Manufacturer/ModelHitachi HD2300 Accelerating Voltage 200 kV Objective Aperture #2Condenser Lens 1 Setting 1.672 Condenser Lens 2 Setting 1.747Approximate Objective Lens Setting 5.86 ZC Mode Projector Lens 1.149 TEMode Projector Lens 0.7 Image Acquisition Pixel Resolution 1280 × 960Acquisition Time 20 sec. (×4

For TEM analysis the sample grids can be transferred to a Hitachi HF2000transmission electron microscope. Transmitted electron images can beacquired at appropriate magnifications. The relevant instrument settingsused during image acquisition can be those given below.

Transmission Electron Instrument Microscope Manufacturer/Model HitachiHF2000 Accelerating Voltage 200 kV Condenser Lens 1 0.78 Condenser Lens2 0 Objective Lens 6.34 Condenser Lens Aperture #1 Objective LensAperture for imaging #3 Selective Area Aperture for SAD N/ABasic Protocols for Forming and Coating Syringe Barrels

The pharmaceutical packages or other vessels tested in the subsequentworking examples were formed and coated according to the followingexemplary protocols, except as otherwise indicated in individualexamples. Particular parameter values given in the following basicprotocols, for example the electric power and gaseous reactant orprocess gas flow, are typical values. When parameter values were changedin comparison to these typical values, this will be indicated in thesubsequent working examples. The same applies to the type andcomposition of the gaseous reactant or process gas.

In some instances, the reference characters and Figures mentioned in thefollowing protocols and additional details can be found in U.S. Pat. No.7,985,188.

Protocol for Coating Syringe Barrel Interior with SiO_(x)

The apparatus and protocol generally as found in U.S. Pat. No. 7,985,188were used for coating syringe barrel interiors with an SiO_(x) barriercoating or layer, in some cases with minor variations. A similarapparatus and protocol were used for coating vials with an SiO_(x)barrier coating or layer, in some cases with minor variations.

Protocol for Coating Syringe Barrel Interior with OMCTS PassivationLayer or pH Protective Coating

Syringe barrels already interior coated with a barrier coating or layerof SiO_(x), as previously identified, are further interior coated with apassivation layer or pH protective coating as previously identified,generally following the protocols of U.S. Pat. No. 7,985,188 forapplying the lubricity coating or layer, except with modified conditionsin certain instances as noted in the working examples. The conditionsgiven here are for a COC syringe barrel, and can be modified asappropriate for syringe barrels made of other materials. The apparatusas generally shown in FIG. 4 can be used to hold a syringe barrel withbutt sealing at the base of the syringe barrel.

The syringe barrel is carefully moved into the sealing position over theextended probe or counter electrode 108 and pushed against a plasmascreen. The plasma screen is fit snugly around the probe or counterelectrode 108 insuring good electrical contact. The probe or counterelectrode 108 is grounded to the casing of the RF matching network.

The gas delivery port 110 is connected to a manual ball valve or similarapparatus for venting, a thermocouple pressure gauge and a bypass valveconnected to the vacuum pumping line. In addition, the gas system isconnected to the gas delivery port 110 allowing the gaseous reactant orprocess gas, octamethylcyclotetrasiloxane (OMCTS) (or the specificgaseous reactant or process gas reported for a particular example) to beflowed through the gas delivery port 110 (under process pressures) intothe interior of the syringe barrel.

The gas system is comprised of a commercially available heated mass flowvaporization system that heats the OMCTS to about 100° C. The heatedmass flow vaporization system is connected to liquidoctamethylcyclotetrasiloxane (Alfa Aesar® Part Number A12540, 98%). TheOMCTS flow rate is set to the specific organosilicon precursor flowreported for a particular example. To ensure no condensation of thevaporized OMCTS flow past this point, the gas stream is diverted to thepumping line when it is not flowing into the interior of the COC syringebarrel for processing.

Once the syringe barrel is installed, the vacuum pump valve is opened tothe vessel holder 50 and the interior of the COC syringe barrel. Avacuum pump and blower comprise the vacuum pump system. The pumpingsystem allows the interior of the COC syringe barrel to be reduced topressure(s) of less than 100 mTorr while the gaseous reactant or processgases is flowing at the indicated rates.

Once the base vacuum level is achieved, the vessel holder 50 assembly ismoved into the electrode 160 assembly. The gas stream (OMCTS vapor) isflowed into the gas delivery port 110 (by adjusting the 3-way valve fromthe pumping line to the gas delivery port 110. The plasma for PECVD, ifused, can be generated at reduced pressure and the reduced pressure canbe less than 300 mTorr, optionally less than 200 mTorr, even optionallyless than 100 mTorr. Pressure inside the COC syringe barrel can be, asone example, approximately 140 mTorr as measured by a capacitancemanometer (MKS) installed on the pumping line near the valve thatcontrols the vacuum. In addition to the COC syringe barrel pressure, thepressure inside the gas delivery port 110 and gas system is alsomeasured with the thermocouple vacuum gauge that is connected to the gassystem. This pressure is typically less than 6 Torr.

Once the gas is flowing to the interior of the COC syringe barrel, theRF power supply is turned on to its fixed power level or as otherwiseindicated in a specific example or description. The physical andchemical properties of the passivation layer or pH protective coatingcan be set by setting the ratio of oxidizing gas to the organosiliconprecursor in the gaseous reactant, and/or by setting the electric powerused for generating the plasma. A 600 Watt RF power supply is used (at13.56 MHz) at a fixed power level or as otherwise indicated in aspecific example or description. The RF power supply is connected to anauto match which matches the complex impedance of the plasma (to becreated in the vessel) to the output impedance of the RF power supply.The forward power is as stated and the reflected power is 0 Watts sothat the stated power is delivered to the interior of the vessel. The RFpower supply is controlled by a laboratory timer and the power on timeset to 10 seconds (or a different time stated in a given example).

Upon initiation of the RF power, uniform plasma is established insidethe interior of the vessel. The plasma is maintained for the entirepassivation layer or pH protective coating time, until the RF power isterminated by the timer. The plasma produces a passivation layer or pHprotective coating on the interior of the vessel.

After applying the passivation layer or pH protective coating, the gasflow is diverted back to the vacuum line and the vacuum valve is closed.The vent valve is then opened, returning the interior of the COC syringebarrel to atmospheric pressure (approximately 760 Torr). The treatedvessel is then carefully removed from the vessel holder 50 assembly(after moving the vessel holder 50 assembly out of the electrode 160assembly).

A similar protocol is used, except using apparatus generally like thatof FIG. 1, for applying a passivation layer or pH protective coating tovials.

Protocol for Total Silicon Measurement

This protocol is used to determine the total amount of silicon coatingspresent on the entire vessel wall. A supply of 0.1 N potassium hydroxide(KOH) aqueous solution is prepared, taking care to avoid contact betweenthe solution or ingredients and glass. The water used is purified water,18 M′Ω quality. A Perkin Elmer Optima Model 7300DV ICP-OES instrument isused for the measurement except as otherwise indicated.

Each device (vial, syringe, tube, or the like) to be tested and its capand crimp (in the case of a vial) or other closure are weighed empty to0.001 g, then filled completely with the KOH solution (with noheadspace), capped, crimped, and reweighed to 0.001 g. In a digestionstep, each vial is placed in a sonicating water bath at 40° C. for aminimum of 8-10 hours. The digestion step is carried out toquantitatively remove the silicon coatings from the vessel wall into theKOH solution. After this digestion step, the vials are removed from thesonicating water bath and allowed to cool to room temperature. Thecontents of the vials are transferred into 15 ml ICP tubes. The total Siconcentration is run on each solution by ICP/OES following the operatingprocedure for the ICP/OES.

The total Si concentration is reported as parts per billion of Si in theKOH solution. This concentration represents the total amount of siliconcoatings that were on the vessel wall before the digestion step was usedto remove it.

The total Si concentration can also be determined for fewer than all thesilicon layers on the vessel, as when an SiO_(x) barrier coating orlayer is applied, an SiO_(x)C_(y) second layer (for example, a lubricitylayer or a passivation layer or pH protective coating) is then applied,and it is desired to know the total silicon concentration of just theSiO_(x)C_(y) layer. This determination is made by preparing two sets ofvessels, one set to which only the SiO_(x) layer is applied and theother set to which the same SiO_(x) layer is applied, followed by theSiO_(x)C_(y) layer or other layers of interest. The total Siconcentration for each set of vessels is determined in the same manneras described above. The difference between the two Si concentrations isthe total Si concentration of the SiO_(x)C_(y) second layer.

Protocol for Measuring Dissolved Silicon in a Vessel

In some of the working examples, the amount of silicon dissolved fromthe wall of the vessel by a test solution is determined, in parts perbillion (ppb), for example to evaluate the dissolution rate of the testsolution. This determination of dissolved silicon is made by storing thetest solution in a vessel provided with an SiO_(x) and/or SiO_(x)C_(y)coating or layer under test conditions, then removing a sample of thesolution from the vessel and testing the Si concentration of the sample.The test is done in the same manner as the Protocol for Total SiliconMeasurement, except that the digestion step of that protocol is replacedby storage of the test solution in the vessel as described in thisprotocol. The total Si concentration is reported as parts per billion ofSi in the test solution

Protocol for Determining Average Dissolution Rate

The average dissolution rates reported in the working examples aredetermined as follows. A series of test vessels having a known totalsilicon measurement are filled with the desired test solution analogousto the manner of filling the vials with the KOH solution in the Protocolfor Total Silicon Measurement. (The test solution can be aphysiologically inactive test solution as employed in the presentworking examples or a physiologically active pharmaceutical preparationintended to be stored in the vessels to form a pharmaceutical package).The test solution is stored in respective vessels for several differentamounts of time, then analyzed for the Si concentration in parts perbillion in the test solution for each storage time. The respectivestorage times and Si concentrations are then plotted. The plots arestudied to find a series of substantially linear points having thesteepest slope.

The plot of dissolution amount (ppb Si) versus days decreases in slopewith time. It is believed that the dissolution rate is not flatteningout because the Si layer has been fully digested by the test solution.

For the PC194 test data in Table 10 below, linear plots of dissolutionversus time data are prepared by using a least squares linear regressionprogram to find a linear plot corresponding to the first five datapoints of each of the experimental plots. The slope of each linear plotis then determined and reported as representing the average dissolutionrate applicable to the test, measured in parts per billion of Sidissolved in the test solution per unit of time.

Protocol for Determining Calculated Shelf Life

The calculated shelf life values reported in the working examples beloware determined by extrapolation of the total silicon measurements andaverage dissolution rates, respectively determined as described in theProtocol for Total Silicon Measurement and the Protocol for DeterminingAverage Dissolution Rate. The assumption is made that under theindicated storage conditions the SiO_(x)C_(y) passivation layer or pHprotective coating will be removed at the average dissolution rate untilthe coating is entirely removed. Thus, the total silicon measurement forthe vessel, divided by the dissolution rate, gives the period of timerequired for the test solution to totally dissolve the SiO_(x)C_(y)coating. This period of time is reported as the calculated shelf life.Unlike commercial shelf life calculations, no safety factor iscalculated. Instead, the calculated shelf life is the calculated time tofailure.

It should be understood that because the plot of ppb Si versus hoursdecreases in slope with time, an extrapolation from relatively shortmeasurement times to relatively long calculated shelf lives is believedto be a “worst case” test that tends to underestimate the calculatedshelf life actually obtainable.

SEM Procedure

SEM Sample Preparation: Each syringe sample was cut in half along itslength (to expose the inner or interior surface). The top of the syringe(Luer end) was cut off to make the sample smaller.

The sample was mounted onto the sample holder with conductive graphiteadhesive, then put into a Denton Desk IV SEM Sample Preparation System,and a thin (approximately 50 Å) gold passivation layer or pH protectivecoating was sputtered onto the inner or interior surface of the syringe.The gold passivation layer or pH protective coating is required toeliminate charging of the surface during measurement.

The sample was removed from the sputter system and mounted onto thesample stage of a Jeol JSM 6390 SEM (Scanning Electron Microscope). Thesample was pumped down to at least 1×10⁻⁶ Torr in the samplecompartment. Once the sample reached the required vacuum level, the slitvalve was opened and the sample was moved into the analysis station.

The sample was imaged at a coarse resolution first, then highermagnification images were accumulated. The SEM images provided in theFigures are 5 m edge-to-edge (horizontal and vertical).

AFM (Atomic Force Microscopy) Procedure.

AFM images were collected using a NanoScope III Dimension 3000 machine(Digital Instruments, Santa Barbara, Calif., USA). The instrument wascalibrated against a NIST traceable standard. Etched silicon scanningprobe microscopy (SPM) tips were used. Image processing proceduresinvolving auto-flattening, plane fitting or convolution were employed.One 10 μm×10 μm area was imaged. Roughness analyses were performed andwere expressed in: (1) Root-Mean-Square Roughness, RMS; 2 MeanRoughness, R_(a); and (3) Maximum Height (Peak-to-Valley), R_(max), allmeasured in nm (see Table 5). For the roughness analyses, each samplewas imaged over the 10 μm×10 μm area, followed by three cross sectionsselected by the analyst to cut through features in the 10 μm×10 μmimages. The vertical depth of the features was measures using the crosssection tool. For each cross section, a Root-Mean-Square Roughness (RMS)in nanometers was reported. These RMS values along with the average ofthe three cross sections for each sample are listed in Table 5.

Additional analysis of the 10 μm×10 μm images represented by Examples Q,T and V was carried out. For this analysis three cross sections wereextracted from each image. The locations of the cross sections wereselected by the analyst to cut through features in the images. Thevertical depth of the features was measured using the cross sectiontool.

The Digital Instruments Nanoscope III AFM/STM acquires and stores3-dimensional representations of surfaces in a digital format. Thesesurfaces can be analyzed in a variety of ways.

The Nanoscope III software can perform a roughness analysis of any AFMor STM image. The product of this analysis is a single page reproducingthe selected image in top view. To the upper right of the image is the“Image Statistics” box, which lists the calculated characteristics ofthe whole image minus any areas excluded by a stopband (a box with an Xthrough it). Similar additional statistics can be calculated for aselected portion of the image and these are listed in the “BoxStatistics” in the lower right portion of the page. What follows is adescription and explanation of these statistics.

Image Statistics:

Z Range (R_(p)): The difference between the highest and lowest points inthe image. The value is not corrected for tilt in the plane of theimage; therefore, plane fitting or flattening the data will change thevalue.

Mean: The average of all of the Z values in the imaged area. This valueis not corrected for the tilt in the plane of the image; therefore,plane fitting or flattening the data will change this value.

RMS(R_(q)): This is the standard deviation of the Z values (or RMSroughness) in the image. It is calculated according to the formula:R _(q)={Σ(Z ₁ −Z _(avg))2/N}

where Z_(avg) is the average Z value within the image; Z₁ is the currentvalue of Z; and N is the number of points in the image. This value isnot corrected for tilt in the plane of the image; therefore, planefitting or flattening the data will change this value.

Mean roughness (R_(a)): This is the mean value of the surface relativeto the Center Plane and is calculated using the formula:R _(a)=[1/(L _(x) L _(y))]∫_(o) ^(Ly)∫_(o) ^(Lx) {f(x,y)}dxdywhere f(x,y) is the surface relative to the Center plane, and L_(x) andL_(y) are the dimensions of the surface.

Max height (R_(max)): This is the difference in height between thehighest and lowest points of the surface relative to the Mean Plane.

Surface area: (Optical calculation): This is the area of the3-dimensional surface of the imaged area. It is calculated by taking thesum of the areas of the triangles formed by 3 adjacent data pointsthroughout the image.

Surface area diff: (Optional calculation) This is the amount that theSurface area is in excess of the imaged area. It is expressed as apercentage and is calculated according to the formula:Surface area diff=100[(Surface area/S ₁2−1]

where S₁ is the length (and width) of the scanned area minus any areasexcluded by stopbands.

Center Plane: A flat plane that is parallel to the Mean Plane. Thevolumes enclosed by the image surface above and below the center planeare equal.

Mean Plane: The image data has a minimum variance about this flat plane.It results from a first order least squares fit on the Z data.

WORKING EXAMPLES

The working examples follow. While much of the testing is carried outusing thermoplastic vessels, instead of glass vessels, and protectingbarrier coatings, instead of preventing glass delamination, the testingof the passivation layer or pH protective coating is analogous in eithertype of vessel.

Examples A-D

Syringe samples were produced as follows. A COC 8007 extended barrelsyringe was produced according to the Protocol for Forming COC SyringeBarrel. An SiO_(x) coating or layer was applied to some of the syringesaccording to the Protocol for coating COC Syringe Barrel Interior withSiO_(x). A lubricity and/or passivation layer or pH protective coatingwas applied to the SiO_(x) coated syringes according to the Protocol forCoating COC Syringe Barrel Interior with OMCTS Lubricity Coating,modified as follows. The OMCTS was supplied from a vaporizer, due to itslow volatility. Argon carrier gas was used. The process conditions wereset to the following:

-   -   OMCTS—3 sccm    -   Argon gas—65 sccm    -   Power—6 watts    -   Time—10 seconds

The coater was later determined to have a small leak while producing theL2 samples identified in the Table, which resulted in an estimatedoxygen flow of 1.0 sccm. The L3 samples were produced withoutintroducing oxygen.

Several syringes were then tested for lubricity using a GenesisPackaging Plunger Force Tester (Model SFT-01 Syringe Force Tester,manufactured by Genesis Machinery, Lionville, Pa.) according to theProtocol for Lubricity Testing. Both the initiation force andmaintenance forces (in Newtons) were noted relative to an uncoatedsample, and are reported in Table 1.

Syringes coated with silicone oil were included as a reference sincethis is the current industry standard.

The lubricity coatings produced according to these working examples arealso contemplated to function as passivation layers or pH protectivecoatings or layers to increase the shelf life of the vessels, comparedto similar vessels provided with a barrier coating or layer but nolubricity coating or layer.

Examples E-H

Syringe samples were produced as follows. A COC 8007 extended barrelsyringe was produced according to the Protocol for Forming COC SyringeBarrel. An SiO_(x) passivation layer or pH protective coating wasapplied to the syringe barrels according to the Protocol for Coating COCSyringe Barrel Interior with SiO_(x). A lubricity and/or passivationlayer or pH protective coating was applied to the SiO_(x) coatedsyringes according to the Protocol for Coating COC Syringe BarrelInterior with OMCTS, modified as follows. Argon carrier gas and oxygenwere used where noted in Table 2. The process conditions were set to thefollowing, or as indicated in Table 2:

-   -   OMCTS—3 sccm (when used)    -   Argon gas—7.8 sccm (when used)    -   Oxygen 0.38 sccm (when used)    -   Power—3 watts    -   Power on time—10 seconds

Syringes E and F prepared under these conditions, Syringes G preparedunder these conditions except without a lubricity layer or a passivationlayer or pH protective coating, and Syringes H (a commercial syringecoated with silicone oil) were then tested for lubricity using a GenesisPackaging Plunger Force Tester according to the Protocol for LubricityTesting. Both the initiation force and maintenance forces (in Newtons)were noted relative to an uncoated sample, and are reported in Table 2.Syringes coated with silicone oil were included as a reference sincethis is the current industry standard.

The lubricity results are shown in Table 2 (Initiation Force andMaintenance Force), illustrating under these test conditions as wellthat the lubricity and/or passivation layer or pH protective coating onSyringes E and F markedly improved their lubricity compared to SyringesG which lacked any lubricity and/or passivation layer or pH protectivecoating. The lubricity and/or passivation layer or pH protective coatingon Syringes E and F also markedly improved their lubricity compared toSyringes H which contained the standard lubricity coating or layer inthe industry.

Syringes E, F, and G were also tested to determine total extractablesilicon levels (representing extraction of the organosilicon-based PECVDpassivation layer or pH protective coating) using the Protocol forMeasuring Dissolved Silicon in a Vessel, modified and supplemented asshown in this example.

The silicon was extracted using saline water digestion. The tip of eachsyringe plunger tip, piston, stopper, or seal was covered with PTFE tapeto prevent extracting material from the elastomeric tip material, theninserted into the syringe barrel base. The syringe barrel was filledwith two milliliters of 0.9% aqueous saline solution via a hypodermicneedle inserted through the Luer tip of the syringe. This is anappropriate test for extractables because many prefilled syringes areused to contain and deliver saline solution. The Luer tip was pluggedwith a piece of PTFE beading of appropriate diameter. The syringe wasset into a PTFE test stand with the Luer tip facing up and placed in anoven at 50° C. for 72 hours.

Then, either a static or a dynamic mode was used to remove the salinesolution from the syringe barrel. According to the static mode indicatedin Table 2, the syringe plunger tip, piston, stopper, or seal wasremoved from the test stand, and the fluid in the syringe was decantedinto a vessel. According to the dynamic mode indicated in Table 2, theLuer tip seal was removed and the plunger tip, piston, stopper, or sealwas depressed to push fluid through the syringe barrel and expel thecontents into a vessel. In either case, the fluid obtained from eachsyringe barrel was brought to a volume of 50 ml using 18.2MΩ-cmdeionized water and further diluted 2× to minimize sodium backgroundduring analysis. The CVH barrels contained two milliliters and thecommercial barrels contained 2.32 milliliters.

Next, the fluid recovered from each syringe was tested for extractablesilicon using the Protocol for Measuring Dissolved Silicon in a Vessel.The instrument used was a Perkin Elmer Elan DRC II equipped with a CetacASX-520 autosampler. The following ICP-MS conditions were employed:

-   -   Nebulizer: Quartz Meinhardt    -   Spray Chamber: Cyclonic    -   RF (radio frequency) power: 1550 Watts    -   Argon (Ar) Flow: 15.0 L/min    -   Auxiliary Ar Flow: 1.2 L/min    -   Nebulizer Gas Flow: 0.88 L/min    -   Integration time: 80 sec    -   Scanning mode: Peak hopping    -   RPq (The RPq is a rejection parameter) for Cerium as CeO (m/z        156: <2%

Aliquots from aqueous dilutions obtained from Syringes E, F, and G wereinjected and analyzed for Si in concentration units of micrograms perliter. The results of this test are shown in Table 2. While the resultsare not quantitative, they do indicate that extractables from thelubricity and/or passivation layer or pH protective coating are notclearly higher than the extractables for the SiO_(x) barrier coating orlayer only. Also, the static mode produced far less extractables thanthe dynamic mode, which was expected.

Examples I-K

Syringe samples I, J, and K, employing three different lubricity and/orpassivation layers or pH protective coatings or layers, were produced inthe same manner as for Examples E-H except as follows or as indicated inTable 3:

-   -   OMCTS—2.5 sccm    -   Argon gas—7.6 sccm (when used)    -   Oxygen 0.38 sccm (when used)    -   Power—3 watts    -   Power on time—10 seconds

Syringe I had a three-component passivation layer or pH protectivecoating employing OMCTS, oxygen, and carrier gas. Syringe J had a twocomponent passivation layer or pH protective coating employing OMCTS andoxygen, but no carrier gas. Syringe K had a one-component passivationlayer or pH protective coating (OMCTS only). Syringes I, J, and K werethen tested for lubricity as described for Examples E-H.

The lubricity results are shown in Table 3 (Initiation Force andMaintenance Force). Syringe I with a three-component passivation layeror pH protective coating employing OMCTS, oxygen, and carrier gasprovided the best lubricity results for both initiation force andmaintenance force. Syringe J omitting the carrier gas yieldedintermediate results. Syringe K had a one-component passivation layer orpH protective coating (OMCTS only), and provided the lowest lubricity.This example shows that the addition of both a carrier gas and oxygen tothe process gas improved lubricity under the tested conditions.

The lubricity coatings produced according to these working examples arealso contemplated to function as passivation layers or pH protectivecoatings or layers to increase the shelf life of the vessels, comparedto similar vessels provided with a barrier coating or layer but nolubricity coating or layer.

Examples L-N

Examples I-K using an OMCTS precursor gas were repeated in Examples L-N,except that HMDSO was used as the precursor in Examples L-N. The resultsare shown in Table 3. The results show that for the testedthree-component, two-component, and one-component lubricity coating orlayer, the OMCTS passivation layer or pH protective coating providedlower resistance, thus better lubricity, than the HMDSO passivationlayer or pH protective coating, demonstrating the value of OMCTS as theprecursor gas for lubricity.

The lubricity coatings produced according to these working examples arealso contemplated to function as passivation layers or pH protectivecoatings or layers to increase the shelf life of the vessels, comparedto similar vessels provided with a barrier coating or layer but nolubricity coating or layer.

Examples O-Y

In these examples the surface roughness of the lubricity and/orpassivation layer or pH protective coating was correlated with lubricityand/or protective performance.

OMCTS lubricity coatings or layers were applied with previouslydescribed equipment with the indicated specific process conditions(Table 5) onto one milliliter COC 6013 molded syringe barrels. Plungerforce measurements (F_(i), F_(m)) (Table 5) were performed withpreviously described equipment under the same protocols. Scanningelectron spectroscopy (SEM) photomicrographs (Table 5, FIGS. 9 and 10)and atomic force microscopy (AFM) Root Mean Square (RMS) and otherroughness determinations (Tables 5 and 6) were made using the proceduresindicated below. Average RMS values are taken from three different RMSreadings on the surface. The plunger force tests, AFM and SEM testsreported in table 5 were performed on different samples due to thenature of the individual tests which prohibited a performance of alltests on one sample.

Comparison of F_(i)/F_(m) to SEM photomicrograph to AFM Average RMSvalues clearly indicates that lower plunger forces are realized withnon-continuous, rougher OMCTS plasma-coated surfaces (cf. Samples O to Qvs. R to V).

Further testing was carried out on sister samples Examples W, X, and Y,respectively made under conditions similar to Example Q, T, and V, toshow the F_(i) and F_(m) values corresponding to the AFM roughness data.Example W which has a higher surface roughness (compare Example Q inTable 5) has much lower F_(i) and F_(m) friction values (Table 6) thanExample X or Y. The F_(m) test shown in Table 6 was interrupted beforereaching the measured value of F_(m) for Examples X and Y because theF_(m) value was too high.

The lubricity coatings produced according to these working examples arealso contemplated to function as passivation layers or pH protectivecoatings or layers to increase the shelf life of the vessels, comparedto similar vessels provided with a barrier coating or layer but nolubricity coating or layer.

Summary of Lubricity and/or Protective Measurements

Table 8 shows a summary of the above OMCTS coatings or layers and theirF_(i) and F_(m) values. It should be understood that the initiallubricity and/or passivation layer or pH protective coating work (C-K;roughness not known) was to identify the lowest possible plunger tip,piston, stopper, or seal advancing force attainable. From subsequentmarket input, it was determined that the lowest achievable force was notnecessarily most desirable, for reasons explained in the genericdescription (for example premature release). Thus, the PECVD reactionparameters were varied to obtain a plunger tip, piston, stopper, or sealforce of practical market use.

Example Z: Lubricity and/or Passivation Layer or pH Protective CoatingExtractables

Silicon extractables from syringes were measured using ICP-MS analysisas described in the Protocol for Measuring Dissolved Silicon in aVessel. The syringes were evaluated in both static and dynamicsituations. The Protocol for Measuring Dissolved Silicon in a Vessel,modified as follows, describes the test procedure:

-   -   Syringe filled with 2 ml of 0.9% saline solution    -   Syringe placed in a stand—stored at 50° C. for 72 hours.    -   After 72 hours saline solution test for dissolved silicon    -   Dissolved silicon measured before and after saline solution        expelled through syringe.

The extractable Silicon Levels from a silicone oil coated glass syringeand a Lubricity and/or protective coated and SiO_(x) coated COC syringeare shown in Table 7. Precision of the ICP-MS total silicon measurementis +/−3%.

Comparative Example AA: Dissolution of SiO_(x) Coating Versus pH

The Protocol for Measuring Dissolved Silicon in a Vessel is followed,except as modified here. Test solutions—50 mM buffer solutions at pH 3,6, 7, 8, 9, and 12 are prepared. Buffers are selected having appropriatepKa values to provide the pH values being studied. A potassium phosphatebuffer is selected for pH 3, 7, 8 and 12, a sodium citrate buffer isutilized for pH 6 and tris buffer is selected for pH 9. 3 ml of eachtest solution is placed in borosilicate glass 5 ml pharmaceutical vialsand SiO_(x) coated 5 ml thermoplastic pharmaceutical vials. The vialsare all closed with standard coated stoppers and crimped. The vials areplaced in storage at 20-25° C. and pulled at various time points forinductively coupled plasma spectrometer (ICP) analysis of Si content inthe solutions contained in the vials, in parts per billion (ppb) byweight, for different storage times.

The Protocol for Determining Average Dissolution Rate Si content is usedto monitor the rate of glass dissolution, except as modified here. Thedata is plotted to determine an average rate of dissolution ofborosilicate glass or SiO_(x) coating at each pH condition.Representative plots at pH 6 through 8 are FIGS. 13-15.

The rate of Si dissolution in ppb is converted to a predicted thickness(nm) rate of Si dissolution by determining the total weight of Siremoved, then using a surface area calculation of the amount of vialsurface (11.65 cm²) exposed to the solution and a density of SiO_(x) of2.2 g/cm³. FIG. 16 shows the predicted initial thickness of the SiO_(x)coating required, based on the conditions and assumptions of thisexample (assuming a residual SiO_(x) coating of at least 30 nm at theend of the desired shelf life of two years, and assuming storage at 20to 25° C.). As FIG. 16 shows, the predicted initial thickness of thecoating is about 36 nm at pH 5, about 80 nm at pH 6, about 230 nm at pH7, about 400 nm at pH 7.5, about 750 nm at pH 8, and about 2600 nm at pH9.

The coating thicknesses in FIG. 16 represent atypically harsh casescenarios for pharma and biotech products. Most biotech products andmany pharma products are stored at refrigerated conditions and none aretypically recommended for storage above room temperature. As a generalrule of thumb, storage at a lower temperature reduces the thicknessrequired, all other conditions being equivalent.

The following conclusions are reached, based on this test. First, theamount of dissolved Si in the SiO_(x) coating or glass increasesexponentially with increasing pH. Second, the SiO_(x) coating dissolvesmore slowly than borosilicate glass at a pH lower than 8. The SiO_(x)coating shows a linear, monophasic dissolution over time, whereasborosilicate glass tends to show a more rapid dissolution in the earlyhours of exposure to solutions, followed by a slower linear dissolution.This may be due to surface accumulation of some salts and elements onborosilicate during the forming process relative to the uniformcomposition of the SiO_(x) coating. This result incidentally suggeststhe utility of an SiO_(x) coating on the wall of a borosilicate glassvial to reduce dissolution of the glass at a pH lower than 8. Third,PECVD applied barrier coatings or layers for vials in whichpharmaceutical preparations are stored will need to be adapted to thespecific pharmaceutical preparation and proposed storage conditions (orvice versa), at least in some instances in which the pharmaceuticalpreparation interacts with the barrier coating or layer significantly.

Example BB

An experiment is conducted with vessels coated with SiO_(x)coating+OMCTS lubricity layer, to test the lubricity layer for itsfunctionality as a passivation layer or pH protective coating. Thevessels are 5 mL vials (the vials are normally filled with product to 5mL; their capacity without headspace, when capped, is about 7.5 mL)composed of cyclic olefin co-polymer (COC, Topas® 6013M-07).

Sixty vessels are coated on their interior surfaces with an SiO_(x)coating produced in a plasma enhanced chemical vapor deposition (PECVD)process using a HMDSO precursor gas according to the Protocol forCoating Tube Interior with SiO_(x) set forth above, except thatequipment suitable for coating a vial is used. The following conditionsare used.

-   -   HMDSO flow rate: 0.47 sccm    -   Oxygen flow rate: 7.5 sccm    -   RF power: 70 Watts    -   Coating time: 12 seconds (includes a 2-sec RF power ramp-up        time)

Next the SiO_(x) coated vials are coated over the SiO_(x) with anSiO_(x)C_(y) coating produced in a PECVD process using an OMCTSprecursor gas according to the Protocol for Coating COC Syringe BarrelInterior with OMCTS Lubricity Coating set forth above, except that thesame coating equipment is used as for the SiO_(x) coating. Thus, thespecial adaptations in the protocol for coating a syringe are not used.The following conditions are used.

-   -   OMCTS flow rate: 2.5 sccm    -   Argon flow rate: 10 sccm    -   Oxygen flow rate: 0.7 sccm    -   RF power: 3.4 Watts    -   Coating time: 5 seconds

Eight vials are selected and the total deposited quantity of PECVDcoating (SiO_(x)+SiO_(x)C_(y)) is determined with a Perkin Elmer OptimaModel 7300DV ICP-OES instrument, using the Protocol for Total SiliconMeasurement set forth above. This measurement determines the totalamount of silicon in both coatings, and does not distinguish between therespective SiO_(x) and SiO_(x)C_(y) coatings. The results are shownbelow.

Quantity of SiO_(x) + Lubricity layer on Vials Vial Total Silicon ug/L 113844 2 14878 3 14387 4 13731 5 15260 6 15017 7 15118 8 12736 Mean 14371StdDev 877

In the following work, except as indicated otherwise in this example,the Protocol for Determining Average Dissolution Rate is followed. Twobuffered pH test solutions are used in the remainder of the experiment,respectively at pH 4 and pH 8 to test the effect of pH on dissolutionrate. Both test solutions are 50 mM buffers using potassium phosphate asthe buffer, diluted in water for injection (WFI) (0.1 um sterilized,filtered). The pH is adjusted to pH 4 or 8, respectively, withconcentrated nitric acid.

25 vials are filled with 7.5 ml per vial of pH 4 buffered test solutionand 25 other vials are filled with 7.5 ml per vial of pH 4 buffered testsolution (note the fill level is to the top of the vial—no head space).The vials are closed using prewashed butyl stoppers and aluminum crimps.The vials at each pH are split into two groups. One group at each pHcontaining 12 vials is stored at 4° C. and the second group of 13 vialsis stored at 23° C.

The vials are sampled at Days 1, 3, 6, and 8. The Protocol for MeasuringDissolved Silicon in a Vessel is used, except as otherwise indicated inthis example. The analytical result is reported on the basis of partsper billion of silicon in the buffered test solutions of each vial. Adissolution rate is calculated in terms of parts per billion per day asdescribed above in the Protocol for Determining Average DissolutionRate. The results at the respective storage temperatures follow:

Shelf Life Conditions 23° C. Vial SiOx + Lubricity Vial SiOx + LubricityCoating at pH 4 Coating at pH 8 Si Dissolution Rate 31 7 (PPB/day)

Shelf Life Conditions 4° C. Vial SiOx + Lubricity Vial SiOx + LubricityCoating at pH 4 Coating at pH 8 Si Dissolution Rate 7 11 (PPB/day)

The observations of Si dissolution versus time for the OMCTS-basedcoating at pH8 and pH 4 indicate the pH 4 rates are higher at ambientconditions. Thus, the pH 4 rates are used to determine how much materialwould need to be initially applied to leave a coating of adequatethickness at the end of the shelf life, taking account of the amount ofthe initial coating that would be dissolved. The results of thiscalculation are:

Shelf Life Calculation Vial with SiOx + Lubricity Coating at pH 4 SiDissolution Rate (PPB/day) 31 Mass of Coating Tested (Total Si) 14,371Shelf Life (days) at 23° C. 464 Shelf Life (years) at 23° C. 1.3Required Mass of Coating (Total Si) -- 2-years 22,630 Required Mass ofCoating (Total Si) -- 3-years 33,945

Based on this calculation, the OMCTS lubricity layer needs to be about2.5 times thicker—resulting in dissolution of 33945 ppb versus the14,371 ppb representing the entire mass of coating tested—to achieve a3-year calculated shelf life.

Example CC

The results of Comparative Example AA and Example BB above can becompared as follows, where the “lubricity layer” is the coating ofSiO_(x)C_(y) referred to in Example BB.

Shelf Life Conditions -- pH 8 and 23° C. Vial with Vial with SiOx + SiOxLubricity Coating Si Dissolution Rate 1,250 7 (PPB/day)

This data shows that the silicon dissolution rate of SiO_(x) alone isreduced by more than 2 orders of magnitude at pH 8 in vials also coatedwith SiO_(x)C_(y) coatings.

Another comparison is shown by the following data from several differentexperiments carried out under similar accelerated dissolutionconditions, of which the 1-day data is also presented in FIG. 17.

Silicon Dissolution with pH 8 at 40° C. (ug/L) Vial Coating 1 2 3 10Description day days days 4 days 7 days days 15 days A. SiO_(x) made 165211 226 252 435 850 1,364 with HMDSO Plasma + Si_(w)O_(x)C_(y) or itsequivalent SiO_(x)C_(y) made with OMCTS Plasma B. Si_(w)O_(x)C_(y) or109 107 76 69 74 158 198 its equivalent SiO_(x)C_(y) made with OMCTSPlasma C. SiO_(x) made 2,504 4,228 5,226 5,650 9,292 10,177 9,551 withHMDSO Plasma D. SiO_(x) made 1,607 1,341 3,927 10,182 18,148 20,44621,889 with HMDSO Plasma + Si_(w)O_(x)C_(y) or its equivalentSiO_(x)C_(y) made with HMDSO Plasma E. Si_(w)O_(x)C_(y) or 1,515 1,7311,813 1,743 2,890 3,241 3,812 its equivalent SiO_(x)C_(y) made withHMDSO Plasma

FIG. 17 and Row A (SiO_(x) with OMCTS coating) versus C (SiO_(x) withoutOMCTS coating) show that the OMCTS lubricity layer is also an effectivepassivation layer or pH protective coating to the SiO_(x) coating at pH8. The OMCTS coating reduced the one-day dissolution rate from 2504 ug/L(“u” or p or the Greek letter “mu” as used herein are identical, and areabbreviations for “micro”) to 165 ug/L. This data also shows that anHMDSO-based Si_(w)O_(x)C_(y) (or its equivalent SiO_(x)C_(y)) overcoat(Row D) provided a far higher dissolution rate than an OMCTS-basedSi_(w)O_(x)C_(y) (or its equivalent SiO_(x)C_(y)) overcoat (Row A). Thisdata shows that a substantial benefit can be obtained by using a cyclicprecursor versus a linear one.

Example DD

Samples 1-6 as listed in Table 9 were prepared as described in ExampleAA, with further details as follows.

A cyclic olefin copolymer (COC) resin was injection molded to form abatch of 5 ml vials. Silicon chips were adhered with double-sidedadhesive tape to the internal walls of the vials. The vials and chipswere coated with a two layer coating by plasma enhanced chemical vapordeposition (PECVD). The first layer was composed of SiO_(x) with barriercoating or layer properties as defined in the present disclosure, andthe second layer was an SiO_(x)C_(y) passivation layer or pH protectivecoating.

A precursor gas mixture comprising OMCTS, argon, and oxygen wasintroduced inside each vial. The gas inside the vial was excited betweencapacitively coupled electrodes by a radio-frequency (13.56 MHz) powersource as described in connection with FIGS. 4-6. The monomer flow rate(F_(m)) in units of sccm, oxygen flow rate (F_(o)) in units of sccm,argon flowrate in sccm, and power (W) in units of watts are shown inTable 9.

A composite parameter, W/FM in units of kJ/kg, was calculated fromprocess parameters W, F_(m), F_(o) and the molecular weight, M in g/mol,of the individual gas species. W/FM is defined as the energy input perunit mass of polymerizing gases. Polymerizing gases are defined as thosespecies that are incorporated into the growing coating such as, but notlimited to, the monomer and oxygen. Non-polymerizing gases, by contrast,are those species that are not incorporated into the growing coating,such as but not limited to argon, helium and neon.

In this test, PECVD processing at high W/FM is believed to have resultedin higher monomer fragmentation, producing organosiloxane coatings withhigher cross-link density. PECVD processing at low W/FM, by comparison,is believed to have resulted in lower monomer fragmentation producingorganosiloxane coatings with a relatively lower cross-link density.

The relative cross-link density of samples 5, 6, 2, and 3 was comparedbetween different coatings by measuring FTIR absorbance spectra. Thespectra of samples 5, 6, 2, and 3 are provided in FIGS. 20-23. In eachspectrum, the ratio of the peak absorbance at the symmetric stretchingmode (1000-1040 cm⁻¹) versus the peak absorbance at the asymmetricstretching mode (1060-1100 cm⁻¹) of the Si—O—Si bond was measured, andthe ratio of these two measurements was calculated, all as shown inTable 9. The respective ratios were found to have a linear correlationto the composite parameter W/FM as shown in FIGS. 18 and 19.

A qualitative relation—whether the coating appeared oily (shiny, oftenwith irridescence) or non-oily (non-shiny) when applied on the siliconchips—was also found to correlate with the W/FM values in Table 9. Oilyappearing coatings deposited at lower W/FM values, as confirmed by Table9, are believed to have a lower crosslink density, as determined bytheir lower sym/asym ratio, relative to the non-oily coatings that weredeposited at higher W/FM and a higher cross-link density. The onlyexception to this general rule of thumb was sample 2 in Table 9. It isbelieved that the coating of sample 2 exhibited a non-oily appearancebecause it was was too thin to see. Thus, an oilyness observation wasnot reported in Table 9 for sample 2. The chips were analyzed by FTIR intransmission mode, with the infrared spectrum transmitted through thechip and sample coating, and the transmission through an uncoated nullchip subtracted.

Non-oily organosiloxane layers produced at higher W/FM values, whichprotect the underlying SiO_(x) coating from aqueous solutions atelevated pH and temperature, were preferred because they provided lowerSi dissolution and a longer shelf life, as confirmed by Table 9. Forexample, the calculated silicon dissolution by contents of the vial at apH of 8 and 40° C. was reduced for the non-oily coatings, and theresulting shelf life was 1381 days in one case and 1147 days in another,as opposed to the much shorter shelf lives and higher rates ofdissolution for oily coatings. Calculated shelf life was determined asshown for Example AA. The calculated shelf life also correlated linearlyto the ratio of symmetric to asymmetric stretching modes of the Si—O—Sibond in organosiloxane passivation layers or pH protective coatings.

Sample 6 can be particularly compared to Sample 5. An organosiloxane, pHpassivation layer or pH protective coating was deposited according tothe process conditions of sample 6 in Table 9. The coating was depositedat a high W/FM. This resulted in a non-oily coating with a high Si—O—Sisym/asym ratio of 0.958, which resulted in a low rate of dissolution of84.1 ppb/day (measured by the Protocol for Determining AverageDissolution Rate) and long shelf life of 1147 days (measured by theProtocol for Determining Calculated Shelf Life). The FTIR spectra ofthis exhibits a relatively similar asymmetric Si—O—Si peak absorbancecompared to the symmetric Si—O—Si peak absorbance. This is an indicationof a higher cross-link density coating, which is a preferredcharacteristic for pH protection and long shelf life.

An organosiloxane pH passivation layer or pH protective coating wasdeposited according to the process conditions of sample 5 in Table 9.The coating was deposited at a moderate W/FM. This resulted in an oilycoating with a low Si—O—Si sym/asym ratio of 0.673, which resulted in ahigh rate of dissolution of 236.7 ppb/day (following the Protocol forDetermining Average Dissolution Rate) and shorter shelf life of 271 days(following the Protocol for Determining Calculated Shelf Life). The FTIRspectrum of this coating is shown in FIG. 20, which exhibits arelatively high asymmetric Si—O—Si peak absorbance compared to thesymmetric Si—O—Si peak absorbance. This is an indication of a lowercross-link density coating, which is contemplated to be an unfavorablecharacteristic for pH protection and long shelf life.

Sample 2 can be particularly compared to Sample 3. A passivation layeror pH protective coating was deposited according to the processconditions of sample 2 in Table 9. The coating was deposited at a lowW/FM. This resulted in a coating that exhibited a low Si—O—Si sym/asymratio of 0.582, which resulted in a high rate of dissolution of 174ppb/day and short shelf life of 107 days. The FTIR spectrum of thiscoating exhibits a relatively high asymmetric Si—O—Si peak absorbancecompared to the symmetric Si—O—Si peak absorbance. This is an indicationof a lower cross-link density coating, which is an unfavorablecharacteristic for pH protection and long shelf life.

An organosiloxane, pH passivation layer or pH protective coating wasdeposited according to the process conditions of sample 3 in Table 9.The coating was deposited at a high W/FM. This resulted in a non-oilycoating with a high Si—O—Si sym/asym ratio of 0.947, which resulted in alow rate of Si dissolution of 79.5 ppb/day (following the Protocol forDetermining Average Dissolution Rate) and long shelf life of 1381 days(following the Protocol for Determining Calculated Shelf Life). The FTIRspectrum of this coating exhibits a relatively similar asymmetricSi—O—Si peak absorbance compared to the symmetric Si—O—Si peakabsorbance. This is an indication of a higher cross-link densitycoating, which is a preferred characteristic for pH protection and longshelf life.

Example EE

An experiment similar to Example BB was carried out, modified asindicated in this example and in Table 10 (where the results aretabulated). 100 5 mL COP vials were made and coated with an SiO_(x)barrier coating or layer and an OMCTS-based passivation layer or pHprotective coating as described previously, except that for Sample PC194only the passivation layer or pH protective coating was applied. Thecoating quantity was again measured in parts per billion extracted fromthe surfaces of the vials to remove the entire passivation layer or pHprotective coating, as reported in Table 10.

In this example, several different coating dissolution conditions wereemployed. The test solutions used for dissolution contained either 0.02or 0.2 wt. % polysorbate-80 surfactant, as well as a buffer to maintaina pH of 8. Dissolution tests were carried out at either 23° C. or 40° C.

Multiple syringes were filled with each test solution, stored at theindicated temperature, and analyzed at several intervals to determinethe extraction profile and the amount of silicon extracted. An averagedissolution rate for protracted storage times was then calculated byextrapolating the data obtained according to the Protocol forDetermining Average Dissolution Rate. The results were calculated asdescribed previously and are shown in Table 10. Of particular note, asshown on Table 10, were the very long calculated shelf lives of thefilled packages provided with a PC 194 passivation layer or pHprotective coating:

21045 days (over 57 years) based on storage at a pH of 8, 0.02 wt. %polysorbate-80 surfactant, at 23° C.;

38768 days (over 100 years) based on storage at a pH of 8, 0.2 wt. %polysorbate-80 surfactant, at 23° C.;

8184 days (over 22 years) based on storage at a pH of 8, 0.02 wt. %polysorbate-80 surfactant, at 40° C.; and

14732 days (over 40 years) based on storage at a pH of 8, 0.2 wt. %polysorbate-80 surfactant, at 40° C.

Referring to Table 10, the longest calculated shelf lives correspondedwith the use of an RF power level of 150 Watts and a corresponding highW/FM value. It is believed that the use of a higher power level causeshigher cross-link density of the passivation layer or pH protectivecoating.

Example FF

Another series of experiments similar to those of Example EE are run,showing the effect of progressively increasing the RF power level on theFTIR absorbance spectrum of the passivation layer or pH protectivecoating. The results are tabulated in Table 11, which in each instanceshows a symmetric/asymmetric ratio greater than 0.75 between the maximumamplitude of the Si—O—Si symmetrical stretch peak normally locatedbetween about 1000 and 1040 cm⁻¹, and the maximum amplitude of theSi—O—Si asymmetric stretch peak normally located between about 1060 andabout 1100 cm⁻¹. Thus, the symmetric/asymmetric ratio is 0.79 at a powerlevel of 20 W, 1.21 or 1.22 at power levels of 40, 60, or 80 W, and 1.26at 100 Watts under otherwise comparable conditions.

The 150 Watt data in Table 11 is taken under somewhat differentconditions than the other data, so it is not directly comparable withthe 20-100 Watt data discussed above. The FTIR data of samples 6 and 8of Table 11 was taken from the upper portion of the vial and the FTIRdata of samples 7 and 9 of Table 11 was taken from the lower portion ofthe vial. Also, the amount of OMCTS was cut in half for samples 8 and 9of Table 11, compared to samples 6 and 7. Reducing the oxygen levelwhile maintaining a power level of 150 W raised the symmetric/asymmetricratio still further, as shown by comparing samples 6 and 7 to samples 8and 9 in Table 11.

It is believed that, other conditions being equal, increasing thesymmetric/asymmetric ratio increases the shelf life of a vessel filledwith a material having a pH exceeding 5.

Table 12 shows the calculated O-Parameters and N-Parameters (as definedin U.S. Pat. No. 8,067,070) for the experiments summarized in Table 11.As Table 12 shows, the O-Parameters ranged from 0.134 to 0.343, and theN-Parameters ranged from 0.408 to 0.623—all outside the ranges claimedin U.S. Pat. No. 8,067,070.

Example GG—Measurement of Contact Angle

The test purpose was to determine the contact angle or surface energy onthe inside surface of two kinds of plastic vials and one kind of glassvial

The specimens that underwent testing and analysis reported here arethree kinds of vials. The specimens are (A) an uncoated COP vial, (B) anSiO_(x)+passivation layer or pH protective coating on a COP vialprepared according to the above Protocol for Coating Syringe BarrelInterior with SiO_(x), followed by the Protocol for Coating SyringeBarrel Interior with OMCTS Passivation layer or pH protective coating,and (C) a glass vial. Small pieces were obtained by cutting the plasticvials or crushing the glass vial in order to test the inside surface.

The analysis instrument for the contact angle tests is the Contact AngleMeter model DM-701, made by Kyowa Interface Science Co., Ltd. (Tokyo,Japan). To obtain the contact angle, five water droplets were depositedon the inside surface of small pieces obtained from each specimen. Thetesting conditions and parameters are summarized below. Both plasticvials were cut and trimmed, while the glass vial needed to be crushed.The best representative pieces for each specimen were selected fortesting. A dropsize of 1 μL (one microliter) was used for all samples.Due to the curvature of the specimens, a curvature correction routinewas used to accurately measure the contact angle. The second table belowcontains the values for the radius of curvature used for each specimen.

Contact Angle Testing Conditions and Parameters Test instrument DM-701Contact Angle Meter Liquid Dispenser 22 gauge stainless steel needleDrop Size 1 μL Test liquid Distilled water Environment Ambient air, roomtemperature

Radius of Curvature for each Vial Specimen Radius of Curvature Specimen(μm, micrometers) COP 9240 COP plus passivation layer or pH protectivecoating 9235 Glass 9900

The contact angle results for each specimen are provided below.

The specimen made from COP plus passivation layer or pH protectivecoating had the highest average contact angle of all tested specimens.The average contact angle for specimen made from COP plus passivationlayer or pH protective coating was 99.1°. The average contact angle forthe uncoated COP specimen was 90.5°. The glass specimen had asignificantly lower average contact angle at 10.6°. This data shows theutility of the passivation layer or pH protective coating to raise thecontact angle of the uncoated COP vessel. It is expected that an SiO_(x)coated vessel without the passivation layer or pH protective coatingwould exhibit a result similar to glass, which shows a hydrophiliccoating relative to the relative to the passivation layer or pHprotective coating.

TABLE Contact Angle Results for Each Tested Specimen (degrees) Std.Specimen Test 1 Test 2 Test 3 Test 4 Test 5 Ave. Dev. COP 88.9 91.9 89.191.4 91.1 90.5 1.4 COP/Pass. 98.9 96.8 102.2 98.3 99.5 99.1 2.0 Glass11.6 10.6 10.1 10.4 10.4 10.6 0.6 Note: “Pass.” means passivation layeror pH protective coating.

Example HH

The purpose of this example was to evaluate the recoverability ordrainage of a slightly viscous aqueous solution from glass, COP andcoated vials,

This study evaluated the recovery of a 30 cps (centipoise) carbohydratesolution in water-for-injection from (A) an uncoated COP vial, (B) anSiO_(x)+passivation layer or pH protective coating on a COP vialprepared according to the above Protocol for Coating Syringe BarrelInterior with SiO_(x), followed by the Protocol for Coating SyringeBarrel Interior with OMCTS Passivation layer or pH protective coating,and (C) a glass vial.

2.0 ml of the carbohydrate solution was pipetted into 30 vials each ofglass, COP and vials coated with a passivation layer or pH protectivecoating. The solution was aspirated from the vials with a 10 ml syringe,through a 23 gauge, 1.5″ needle. The vials were tipped to one side asthe solution was aspirated to maximize the amount recovered. The sametechnique and similar withdrawal time was used for all vials. The vialswere weighed empty, after placing 2.0 ml of the solution to the vial andat the conclusion of aspirating the solution from the vial. The amountdelivered to the vial (A) was determined by subtracting the weight ofthe empty vial from the weight of the vial with the 2.0 ml of solution.The weight of solution not recovered (B) was determined by subtractingthe weight of the empty vial from the weight of the vials afteraspirating the solution from the vial. The percent unrecovered wasdetermined by dividing B by A and multiplying by 100.

It was observed during the aspiration of drug product that the glassvials remained wetted with the solution. The COP vial repelled theliquid and as the solution was aspirated from the vials. This helpedwith recovery but droplets were observed to bead on the sidewalls of thevials during the aspiration. The vials coated with a passivation layeror pH protective coating also repelled the liquid during aspiration butno beading of solution on the sidewalls was observed.

The conclusion was that vials coated with a passivation layer or pHprotective coating do not wet with aqueous solutions as do glass vials,leading to superior recovery of drug product relative to glass. Vialscoated with a passivation layer or pH protective coating were notobserved to cause beading of solution on sidewall during aspiration ofaqueous products therefore coated vials performed better than uncoatedCOP vials in product recovery experiments.

Example II—Glass Delamination

Bi-layer coated (SiO_(x) barrier coating or layer plus passivation layeror pH protective coating) glass vials were subjected to a wide range ofchemical and physical challenges:

-   -   pH 2.5 to 9.5    -   Water for Injection (WFI) contained in the vial;    -   Variety of buffers—acetate, citrate, phosphate and HEPES        contained in the vial;    -   4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid contained in        the vial.    -   Ionic strengths from 0 to 600 milliosmoles per kilogram    -   Tween 80 concentrations up to 2%    -   Temperatures up to 40° C.        No delamination events were observed in these tests. The        bi-layer coating also did not delaminate when subjected to a        liquid nitrogen (−200° C.) freeze—thaw temperature cycle. The        bi-layer coating further did not delaminate when scratched and        then subjected to a liquid nitrogen (−200° C.) freeze—thaw        temperature cycle.

TABLE 1 PLUNGER SLIDING FORCE MEASUREMENTS OF OMCTS-BASED PLASMAPASSIVATION LAYER OR PH PROTECTIVE COATING MADE WITH CARRIER GASLubricity, Carrier passivation Gas layer or pH OMCTS (Ar) protectiveCoating Flow O2 Flow Flow Initiation Maintenance coating Time Rate RateRate Power Force, F_(i) Force, F_(m) Example Type Monomer (sec) (sccm)(sccm) (sccm) (Watts) (N, Kg.) (N, Kg.) A Uncoated n/a n/a n/a n/a n/an/a >11 N >11 N (Control) COC >1.1 Kg. >1.1 Kg. B Silicone oil n/a n/an/a n/a n/a n/a 8.2 N 6.3 N (Industry on COC 0.84 Kg. 0.64 Kg. Standard)C L3 lubricity OMCTS 10 sec 3 0 65 6 4.6 N 4.6 N (without coating or0.47 Kg. 0.47 Kg. Oxygen) layer over SiO_(x) on COC D L2 lubricity OMCTS10 sec 3 1 65 6 4.8 N 3.5 N (with and/or 0.49 Kg. 0.36 Kg. Oxygen)passivation layer or pH protective coating over SiO_(x) on COC

TABLE 2 OMCTS Lubricity and/or passivation layer or pH protectivecoating (E and F) Initiation Maintenance ICPMS OMCTS O₂ Ar Force, F_(i)Force, (μg./ ICPMS Example (sccm) (sccm) (sccm) (N) F_(m) (N) liter)Mode E 3.0 0.38 7.8 4.8 3.5 <5 static F 3.0 0.38 7.8 5.4 4.3 38 dynamicG n/a n/a n/a 13 11 <5 static (SiO_(x) only) H n/a n/a n/a 8.2 6.3(silicone oil)

TABLE 3 OMCTS Lubricity and/or passivation layer or pH protectivecoating Initiation Maintenance OMCTS O₂ Ar Force, F_(i) Force, F_(m)Example (sccm) (sccm) (sccm) (N) (N) I 2.5 0.38 7.6 5.1 4.4 J 2.5 0.38 —7.1 6.2 K 2.5 — — 8.2 7.2

TABLE 4 HMDSO passivation layer or pH protective coating InitiationMaintenance HMDSO O₂ Ar Force, F_(i) Force, F_(m) Example (sccm) (sccm)(sccm) (N) (N) L 2.5 0.38 7.6 9 8.4 M 2.5 0.38 — >11 >11 N 2.5 — — >11>11

TABLE 5 SEM Dep. Micrograph OMCTS Ar/O₂ Power Time Plunger Force (5micronAF AFM RMS Example (sccm) (sccm) (Watts) (sec) F_(i) (lbs, Kg)F_(m) (lbs, Kg) Vertical) (nanometers) O Baseline 2.0 10/0.38 3.5 104.66, 2.11 3.47, 1.57 OMCTS (ave) (ave) P Lubricity FIG. 9 Q 19.6, 9.9,9.4 (Average = 13.0 R High Power 2.0 10/0.38 4.5 10 4.9, 2.2 7.6, 3.4 SOMCTS FIG. 10 T Lubricity 12.5, 8.4, 6.1 (Average = 6.3) U No O₂ OMCTS2.0 10/0   3.4 10 4.9, 2.2 9.7, 4.4 Lubricity (stopped) V 1.9, 2.6, 3.0(Average = 2.3)

TABLE 6 Siloxane Power Dep. Time F_(i) (lb., F_(m) (lb., SiO_(x)/LubCoater Mode Feed Ar/O₂ (W) (Sec.) Kg.) Kg.) Example W SiO_(x): Auto-TubeAuto HMDSO 0 sccm Ar, 37 7 ~ ~ SiO_(x)/Baseline 52.5 in, 90 sccm O₂OMCTS Lub 133.4 cm. Lubricity: Auto-S same OMCTS, 10 sccm Ar 3.4 10 2.9,1.3 3.3, 1.5 2.0 sccm 0.38 sccm O₂ Example X SiO_(x): same same samesame 37 7 ~ ~ SiO_(x)/High Pwr Lubricity: same same same same 4.5 10  5, 2.3 9.5, 4.3 OMCTS Lub stopped Example Y SiO_(x): Auto-Tube samesame 0 sccm Ar, 37 7 ~ ~ SiO_(x)/No O₂ 90 sccm O₂ OMCTS Lub Lubricity:Auto-S same same 10 sccm Ar 3.4 10 5.6,   9.5, 4.3 0 sccm O₂ stopped

TABLE 7 Silicon Extractables Comparison of Lubricity Coatings StaticDynamic Package Type (ug/L) (ug/L) Cyclic Olefin Syringe with CVHoldings SiOCH 70 81 Lubricity Coating Borocilicate Glass Syringe withsilicone oil 825 835

TABLE 8 Summary Table of OMCTS passivation layer or pH protectivecoating from Tables 1, 2, 3 and 5 OMCTS Dep Time Example (sccm) O₂(sccm) Ar (sccm) Power (Watt) (sec) F_(i) (lbs) F_(m) (lbs) C 3.0 0.0065 6 10 1.0 1.0 D 3.0 1.00 65 6 10 1.1 0.8 E 3.0 0.38 7.8 6 10 0.8 1.1 F3.0 0.38 7.8 6 10 1.2 1.0 I 2.5 0.38 7.6 6 10 1.1 1.0 J 2.5 0.38 0.0 610 1.6 1.4 K 2.5 0.00 0.0 6 10 1.8 1.6 O 2.0 0.38 10 3.5 10 4.6 3.5 R2.0 0.38 10 4.5 10 4.9 7.6 U 2.0 0.00 10 3.4 10 4.9 9.7 (stop) W 2.00.38 10 3.4 10 2.9 3.3 X 2.0 0.38 10 4.5 10 5.0 9.5 (stop) Y 2.0 0.00 103.4 10 5.6 9.5 (stop)

TABLE 9 Flow Process Parameters Si Dissolution @ pH 8/40° C. FTIRAbsorbance Rate O₂ Shelf Rate of Si—O—Si sym Si—O—Si Ratio Sam- FlowPower W/FM Total Si life Dissolution stretch asym stretch Si—O—Si plesOMCTS Ar Rate (W) (kJ/kg) (ppb) (days) (ppb/day) (1000-1040 cm⁻¹)(1060-1100 cm⁻¹) (sym/asym) Oilyness 1 3 10 0.5 14 21613 43464 385293.18 0.153 0.219 0.700 YES 2 3 20 0.5 2 3088 7180 107 174.08 0.0110.020 0.582 NA 3 1 20 0.5 14 62533 42252.17 1381 79.53 0.093 0.098 0.947NO 4 2 15 0.5 8 18356 27398 380 187.63 0.106 0.141 0.748 YES 5 3 20 0.514 21613 24699 271 236.73 0.135 0.201 0.673 YES 6 1 10 0.5 14 6253337094 1147 84.1 0.134 0.140 0.958 NO

TABLE 10 OMCTS Argon O₂ Total Si Average Flow Flow Flow Plasma (ppb)Calculated Rate of Rate Rate Rate Power Duration W/FM (OMCTS) Shelf-lifeDissolution Sample (sccm) (sccm) (sccm) (W) (sec) (kJ/kg) layer) (days)(ppb/day) Si Dissolution @ pH 8/23° C./0.02% Process ParametersTween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 21045 3.5 018 1.0 200.5 18 15 77157 42982 1330 32.3 Si Dissolution @ pH 8/23° C./0.2%Process Parameters Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 7366038768 1.9 018 1.0 20 0.5 18 15 77157 42982 665 64.6 048 4 80 2 35 2037507 56520 1074 52.62 Si Dissolution @ pH 8/40° C./0.02% ProcessParameters Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 73660 8184 9 0181.0 20 0.5 18 15 77157 42982 511 84 Si Dissolution @ pH 8/40° C./0.2%Process Parameters Tween ®-80 PC194 0.5 20 0.5 150 20 1223335 7366014732 5 018 1.0 20 0.5 18 15 77157 42982 255 168

TABLE 11 OMCTS Argon O₂ Symmetric Assymetric Flow Flow Flow PlasmaStretch Stretch Rate Rate Rate Power Duration W/FM Peak at Peak atSymmetric/Assymetric Samples (sccm) (sccm) (sccm) (W) (sec) (kJ/kg)1000-1040 cm⁻¹ 1060-1100 cm⁻¹ Ratio ID Process Parameters FTIR Results 11 20 0.5 20 20 85,730 0.0793 0.1007 0.79 2 1 20 0.5 40 20 171,460 0.06190.0507 1.22 3 1 20 0.5 60 20 257,190 0.1092 0.0904 1.21 4 1 20 0.5 80 20342,919 0.1358 0.1116 1.22 5 1 20 0.5 100 20 428,649 0.209 0.1658 1.26 61 20 0.5 150 20 642,973 0.2312 0.1905 1.21 7 1 20 0.5 150 20 642,9730.2324 0.1897 1.23 8 0.5 20 0.5 150 20 1,223,335 0.1713 0.1353 1.27 90.5 20 0.5 150 20 1,223,335 0.1475 0.1151 1.28

TABLE 12 OMCTS Argon O₂ Flow Flow Flow Plasma Rate Rate Rate PowerDuration W/FM Samples (sccm) (sccm) (sccm) (W) (sec) (kJ/kg) O- N- IDProcess Parameters Parameter Parameter 1 1 20 0.5 20 20 85,730 0.3430.436 2 1 20 0.5 40 20 171,460 0.267 0.408 3 1 20 0.5 60 20 257,1900.311 0.457 4 1 20 0.5 80 20 342,919 0.270 0.421 5 1 20 0.5 100 20428,649 0.177 0.406 6 1 20 0.5 150 20 642,973 0.151 0.453 7 1 20 0.5 15020 642,973 0.151 0.448 8 0.5 20 0.5 150 20 1,223,335 0.134 0.623 9 0.520 0.5 150 20 1,223,335 0.167 0.609

While the invention has been illustrated and described in detail in thedrawings and foregoing description, such illustration and descriptionare to be considered illustrative or exemplary and not restrictive; theinvention is not limited to the disclosed embodiments. Other variationsto the disclosed embodiments can be understood and effected by thoseskilled in the art and practicing the claimed invention, from a study ofthe drawings, the disclosure, and the appended claims. In the claims,the word “comprising” does not exclude other elements or steps, and theindefinite article “a” or “an” does not exclude a plurality. The merefact that certain measures are recited in mutually different dependentclaims does not indicate that a combination of these measures cannot beused to advantage. Any reference signs in the claims should not beconstrued as limiting the scope.

The invention claimed is:
 1. A vessel comprising: a thermoplastic wallhaving an interior surface enclosing a lumen; a fluid contained in thelumen having a pH greater than 5 disposed in the lumen; a barriercoating or layer of SiO_(x), in which x is between 1.5 and 2.9, thebarrier coating or layer applied by PECVD, positioned between theinterior surface of the thermoplastic wall and the fluid, and supportedby the thermoplastic wall, the barrier coating or layer having thecharacteristic of being subject to being measurably diminished inbarrier improvement factor in less than six months as a result of attackby the fluid; and a passivation layer or pH protective coating ofSiO_(x)C_(y), in which x is between 0.5 and 2.4 and y is between 0.6 and3, the passivation layer or pH protective coating applied by PECVD,positioned between the barrier coating or layer and the fluid, andsupported by the thermoplastic wall, the passivation layer or pHprotective coating being effective to keep the barrier coating or layerat least substantially undissolved as a result of attack by the fluidfor a period of at least six months.
 2. The vessel of claim 1, in whichat least a portion of the wall of the vessel comprises or consistsessentially of a polyolefin, a cyclic olefin polymer, a cyclic olefincopolymer, a polyester, a polycarbonate, polylactic acid, or acombination or copolymer of these.
 3. The vessel of claim 1, in whichthe vessel comprises a syringe barrel, a cartridge, a vial, or a blisterpackage.
 4. The vessel of claim 1, in which the fluid composition has apH up to
 9. 5. The vessel of claim 1, in which the rate of erosion ofthe passivation layer or pH protective coating, if directly contacted bya fluid composition having a pH of 8, is less than 20% of the rate oferosion of the barrier coating or layer, if directly contacted by thesame fluid composition under the same conditions.
 6. The vessel of claim1, in which the fluid composition removes the passivation layer or pHprotective coating at a rate of 1 nm or less of passivation layer or pHprotective coating thickness per 44 hours of contact.
 7. The vessel ofclaim 1, in which the silicon dissolution rate by a 50 mM potassiumphosphate buffer diluted in water for injection, adjusted to pH 8 withconcentrated nitric acid, and containing 0.2 wt. % polysorbate-80surfactant from the vessel is less than 170 ppb/day.
 8. The vessel ofclaim 1, in which the calculated shelf life (total Si/Si dissolutionrate) is more than 1 year and less than 5 years.
 9. The vessel of claim1, wherein said fluid composition comprises a drug.
 10. The vessel ofclaim 1, in which the fluid composition comprises a member selected fromthe group consisting of: Inhalation Anesthetics Aliflurane ChloroformCyclopropane Desflurane (Suprane) Diethyl Ether Enflurane (Ethrane)Ethyl Chloride Ethylene Halothane (Fluothane) Isoflurane (Forane,Isoflo) Isopropenyl vinyl ether Methoxyflurane methoxyflurane,Methoxypropane Nitrous Oxide Roflurane Sevoflurane (Sevorane, Ultane,Sevoflo) Teflurane Trichloroethylene Vinyl Ether Xenon Injectable DrugsAblavar (Gadofosveset Trisodium Injection) Abarelix DepotAbobotulinumtoxin A Injection (Dysport) ABT-263 ABT-869 ABX-EFGAccretropin (Somatropin Injection) Acetadote (Acetylcysteine Injection)Acetazolamide Injection (Acetazolamide Injection) AcetylcysteineInjection (Acetadote) Actemra (Tocilizumab Injection) Acthrel(Corticorelin Ovine Triflutate for Injection) Actummune ActivaseAcyclovir for Injection (Zovirax Injection) Adacel Adalimumab Adenoscan(Adenosine Injection) Adenosine Injection (Adenoscan) AdrenaclickAdreView (lobenguane 1123 Injection for Intravenous Use) AfluriaAk-Fluor (Fluorescein Injection) Aldurazyme (Laronidase) AlgluceraseInjection (Ceredase) Alkeran Injection (Melphalan FlcI Injection)Allopurinol Sodium for Injection (Aloprim) Aloprim (Allopurinol Sodiumfor Injection) Alprostadil Alsuma (Sumatriptan Injection) ALTU-238 AminoAcid Injections Aminosyn Apidra Apremilast Alprostadil Dual ChamberSystem for Injection (Caverject Impulse) AMG 009 AMG 076 AMG 102 AMG 108AMG 114 AMG 162 AMG 220 AMG 221 AMG 222 AMG 223 AMG 317 AMG 379 AMG 386AMG 403 AMG 477 AMG 479 AMG 517 AMG 531 AMG 557 AMG 623 AMG 655 AMG 706AMG 714 AMG 745 AMG 785 AMG 811 AMG 827 AMG 837 AMG 853 AMG 951Amiodarone HCl Injection (Amiodarone HCl Injection) Amobarbital SodiumInjection (Amytal Sodium) Amytal Sodium (Amobarbital Sodium Injection)Anakinra Anti-Abeta Anti-Beta7 Anti-Beta20 Anti-CD4 Anti-CD20 Anti-CD40Anti-IFNalpha Anti-IL13 Anti-OX40L Anti-oxLDS Anti-NGF Anti-NRP1 ArixtraAmphadase (Flyaluronidase Inj) Ammonul (Sodium Phenylacetate and SodiumBenzoate Injection) Anaprox Anzemet Injection (Dolasetron MesylateInjection) Apidra (Insulin Glulisine [rDNA origin] Inj) Apomab Aranesp(darbepoetin alfa) Argatroban (Argatroban Injection) ArginineHydrochloride Injection (R-Gene 10) Aristocort Aristospan ArsenicTrioxide Injection (Trisenox) Articane HCl and Epinephrine Injection(Septocaine) Arzerra (Ofatumumab Injection) Asclera (PolidocanolInjection) Ataluren Ataluren-DMD Atenolol Inj (Tenormin I.V. Injection)Atracurium Besylate Injection (Atracurium Besylate Injection) AvastinAzactam Injection (Aztreonam Injection) Azithromycin (ZithromaxInjection) Aztreonam Injection (Azactam Injection) Baclofen Injection(Lioresal Intrathecal) Bacteriostatic Water (Bacteriostatic Water forInjection) Baclofen Injection (Lioresal Intrathecal) Bal in Oil Ampules(Dimercarprol Injection) BayHepB BayTet Benadryl BendamustineHydrochloride Injection (Treanda) Benztropine Mesylate Injection(Cogentin) Betamethasone Injectable Suspension (Celestone Soluspan)Bexxar Bicillin C-R 900/300 (Penicillin G Benzathine and Penicillin GProcaine Injection) Blenoxane (Bleomycin Sulfate Injection) BleomycinSulfate Injection (Blenoxane) Boniva Injection (Ibandronate SodiumInjection) Botox Cosmetic (OnabotulinumtoxinA for Injection) BR3-FCBravelle (Urofollitropin Injection) Bretylium (Bretylium TosylateInjection) Brevital Sodium (Methohexital Sodium for Injection) BrethineBriobacept BTT-1 023 Bupivacaine HCl Byetta Ca-DTPA (Pentetate CalciumTrisodium Inj) Cabazitaxel Injection (Jevtana) Caffeine Alkaloid(Caffeine and Sodium Benzoate Injection) Calcijex Injection (Calcitrol)Calcitrol (Calcijex Injection) Calcium Chloride (Calcium ChlorideInjection 10%) Calcium Disodium Versenate (Edetate Calcium DisodiumInjection) Campath (Altemtuzumab) Camptosar Injection (IrinotecanHydrochloride) Canakinumab Injection (Haris) Capastat Sulfate(Capreomycin for Injection) Capreomycin for Injection (Capastat Sulfate)Cardiolite (Prep kit for Technetium Tc99 Sestamibi for Injection)Carticel Cathflo Cefazolin and Dextrose for Injection (CefazolinInjection) Cefepime Hydrochloride Cefotaxime Ceftriaxone CerezymeCarnitor Injection Caverject Celestone Soluspan Celsior Cerebyx(Fosphenytoin Sodium Injection) Ceredase (Alglucerase Injection) Ceretec(Technetium Tc99m Exametazime Injection) Certolizumab CF-1 01Chloramphenicol Sodium Succinate (Chloramphenicol Sodium SuccinateInjection) Chloramphenicol Sodium Succinate Injection (ChloramphenicolSodium Succinate) Cholestagel (Colesevelam HCL) Choriogonadotropin AlfaInjection (Ovidrel) Cimzia Cisplatin (Cisplatin Injection) Clolar(Clofarabine Injection) Clomiphine Citrate Clonidine Injection(Duraclon) Cogentin (Benztropine Mesylate Injection) ColistimethateInjection (Coly-Mycin M) Coly-Mycin M (Colistimethate Injection) CompathConivaptan Hcl Injection (Vaprisol) Conjugated Estrogens for Injection(Premarin Injection) Copaxone Corticorelin Ovine Triflutate forInjection (Acthrel) Corvert (Ibutilide Fumarate Injection) Cubicin(Daptomycin Injection) CF-101 Cyanokit (Hydroxocobalamin for Injection)Cytarabine Liposome Injection (DepoCyt) Cyanocobalamin Cytovene(ganciclovir) D.H.E. 45 Dacetuzumab Dacogen (Decitabine Injection)Dalteparin Dantrium IV (Dantrolene Sodium for Injection) DantroleneSodium for Injection (Dantrium IV) Daptomycin Injection (Cubicin)Darbepoietin Alfa DDAVP Injection (Desmopressin Acetate Injection)Decavax Decitabine Injection (Dacogen) Dehydrated Alcohol (DehydratedAlcohol Injection) Denosumab Injection (Prolia) Delatestryl DelestrogenDelteparin Sodium Depacon (Valproate Sodium Injection) Depo Medrol(Methylprednisolone Acetate Injectable Suspension) DepoCyt (CytarabineLiposome Injection) DepoDur (Morphine Sulfate XR Liposome Injection)Desmopressin Acetate Injection (DDAVP Injection) Depo-EstradiolDepo-Provera 104 mg/ml Depo-Provera 150 mg/ml Depo-TestosteroneDexrazoxane for Injection, Intravenous Infusion Only (Totect)Dextrose/Electrolytes Dextrose and Sodium Chloride Inj (Dextrose 5% in0.9% Sodium Chloride) Dextrose Diazepam Injection (Diazepam Injection)Digoxin Injection (Lanoxin Injection) Dilaudid-HP (HydromorphoneHydrochloride Injection) Dimercarprol Injection (Bal in Oil Ampules)Diphenhydramine Injection (Benadryl Injection) Dipyridamole Injection(Dipyridamole Injection) DMOAD Docetaxel for Injection (Taxotere)Dolasetron Mesylate Injection (Anzemet Injection) Doribax (Doripenem forInjection) Doripenem for Injection (Doribax) Doxercalciferol Injection(Hectorol Injection) Doxil (Doxorubicin Hoi Liposome Injection)Doxorubicin Hoi Liposome Injection (Doxil) Duraclon (ClonidineInjection) Duramorph (Morphine Injection) Dysport (Abobotulinumtoxin AInjection) Ecallantide Injection (Kalbitor) EC-Naprosyn (naproxen)Edetate Calcium Disodium Injection (Calcium Disodium Versenate) Edex(Alprostadil for Injection) Engerix Edrophonium Injection (Enlon)Eliglustat Tartate Eloxatin (Oxaliplatin Injection) Emend Injection(Fosaprepitant Dimeglumine Injection) Enalaprilat Injection (EnalaprilatInjection) Enlon (Edrophonium Injection) Enoxaparin Sodium Injection(Lovenox) Eovist (Gadoxetate Disodium Injection) Enbrel (etanercept)Enoxaparin Epicel Epinepherine Epipen Epipen Jr. Epratuzumab ErbituxErtapenem Injection (Invanz) Erythropoieten Essential Amino AcidInjection (Nephramine) Estradiol Cypionate Estradiol Valerate EtanerceptExenatide Injection (Byetta) Evlotra Fabrazyme (Adalsidase beta)Famotidine Injection FDG (Fludeoxyglucose F 18 Injection) Feraheme(Ferumoxytol Injection) Feridex I.V. (Ferumoxides Injectable Solution)Fertinex Ferumoxides Injectable Solution (Feridex I.V.) FerumoxytolInjection (Feraheme) Flagyl Injection (Metronidazole Injection) FluarixFludara (Fludarabine Phosphate) Fludeoxyglucose F 18 Injection (FDG)Fluorescein Injection (Ak-Fluor) Follistim AQ Cartridge (FollitropinBeta Injection) Follitropin Alfa Injection (Gonal-f RFF) FollitropinBeta Injection (Follistim AQ Cartridge) Folotyn (Pralatrexate Solutionfor Intravenous Injection) Fondaparinux Forteo (Teriparatide (rDNAorigin) Injection) Fostamatinib Fosaprepitant Dimeglumine Injection(Emend Injection) Foscarnet Sodium Injection (Foscavir) Foscavir(Foscarnet Sodium Injection) Fosphenytoin Sodium Injection (Cerebyx)Fospropofol Disodium Injection (Lusedra) Fragmin Fuzeon (enfuvirtide)GA101 Gadobenate Dimeglumine Injection (Multihance) GadofosvesetTrisodium Injection (Ablavar) Gadoteridol Injection Solution (ProHance)Gadoversetamide Injection (OptiMARK) Gadoxetate Disodium Injection(Eovist) Ganirelix (Ganirelix Acetate Injection) Gardasil GC1 008 GDFDGemtuzumab Ozogamicin for Injection (Mylotarg) Genotropin GentamicinInjection GENZ-1 12638 Golimumab Injection (Simponi Injection) tonal-fRFF (Follitropin Alfa Injection) Granisetron Hydrochloride (KytrilInjection) Gentamicin Sulfate Glatiramer Acetate Glucagen Glucagon HAE1Haldol (Haloperidol Injection) Havrix Hectorol Injection(Doxercalciferol Injection) Hedgehog Pathway Inhibitor Heparin HerceptinhG-CSF Humalog Human Growth Hormone Humatrope Hu Max Humegon HumiraHumulin Ibandronate Sodium Injection (Boniva Injection) Ibuprofen LysineInjection (NeoProfen) Ibutilide Fumarate Injection (Corvert) IdamycinPFS (Idarubicin Hydrochloride Injection) Idarubicin HydrochlorideInjection (Idamycin PFS) Haris (Canakinumab Injection) Imipenem andCilastatin for Injection (Primaxin I.V.) Imitrex Incobotulinumtoxin Afor Injection (Xeomin) Increlex (Mecasermin [rDNA origin] Injection)Indocin IV (Indomethacin Inj) Indomethacin Inj (Indocin IV) InfanrixInnohep Insulin Insulin Aspart [rDNA origin] Inj (NovoLog) InsulinGlargine [rDNA origin] Injection (Lantus) Insulin Glulisine [rDNAorigin] Inj (Apidra) Interferon alfa-2b, Recombinant for Injection(Intron A) Intron A (Interferon alfa-2b, Recombinant for Injection)Invanz (Ertapenem Injection) Invega Sustenna (Paliperidone PalmitateExtended-Release Injectable Suspension) Invirase (saquinavir mesylate)lobenguane 1123 Injection for Intravenous Use (AdreView) IopromideInjection (Ultravist) Ioversol Injection (Optiray Injection) Iplex(Mecasermin Rinfabate [rDNA origin] Injection) Iprivask IrinotecanHydrochloride (Camptosar Injection) Iron Sucrose Injection (Venofer)Istodax (Romidepsin for Injection) Itraconazole Injection (SporanoxInjection) Jevtana (Cabazitaxel Injection) Jonexa Kalbitor (EcallantideInjection) KCL in DSNS (Potassium Chloride in 5% Dextrose and SodiumChloride Injection) KCL in D5W KCL in NS Kenalog 10 Injection(Triamcinolone Acetonide Injectable Suspension) Kepivance (Palifermin)Keppra Injection (Levetiracetam) Keratinocyte KFG Kinase InhibitorKineret (Anakinra) Kinlytic (Urokinase Injection) Kinrix Klonopin(clonazepam) Kytril Injection (Granisetron Hydrochloride) lacosamideTablet and Injection (Vimpat) Lactated Ringer's Lanoxin Injection(Digoxin Injection) Lansoprazole for Injection (Prevacid I.V.) LantusLeucovorin Calcium (Leucovorin Calcium Injection) Lente (L) LeptinLevemir Leukine Sargramostim Leuprolide Acetate LevothyroxineLevetiracetam (Keppra Injection) Lovenox Levocarnitine Injection(Carnitor Injection) Lexiscan (Regadenoson Injection) LioresalIntrathecal (Baclofen Injection) Liraglutide [rDNA] Injection (Victoza)Lovenox (Enoxaparin Sodium Injection) Lucentis (Ranibizumab Injection)Lumizyme Lupron (Leuprolide Acetate Injection) Lusedra (FospropofolDisodium Injection) Maci Magnesium Sulfate (Magnesium Sulfate Injection)Mannitol Injection (Mannitol IV) Marcaine (Bupivacaine Hydrochloride andEpinephrine Injection) Maxipime (Cefepime Hydrochloride for Injection)MDP Multidose Kit of Technetium Injection (Technetium Tc99m MedronateInjection) Mecasermin [rDNA origin] Injection (Increlex) MecaserminRinfabate [rDNA origin] Injection (Iplex) Melphalan Hcl Injection(Alkeran Injection) Methotrexate Menactra Menopur (MenotropinsInjection) Menotropins for Injection (Repronex) Methohexital Sodium forInjection (Brevital Sodium) Methyldopate Hydrochloride Injection,Solution (Methyldopate Hcl) Methylene Blue (Methylene Blue Injection)Methylprednisolone Acetate Injectable Suspension (Depo Medrol) MetMabMetoclopramide Injection (Reglan Injection) Metrodin (Urofollitropin forInjection) Metronidazole Injection (Flagyl Injection) MiacalcinMidazolam (Midazolam Injection) Mimpara (Cinacalet) Minocin Injection(Minocycline Inj) Minocycline Inj (Minocin Injection) MipomersenMitoxantrone for Injection Concentrate (Novantrone) Morphine Injection(Duramorph) Morphine Sulfate XR Liposome Injection (DepoDur) MorrhuateSodium (Morrhuate Sodium Injection) Motesanib Mozobil (PlerixaforInjection) Multihance (Gadobenate Dimeglumine Injection) MultipleElectrolytes and Dextrose Injection Multiple Electrolytes InjectionMylotarg (Gemtuzumab Ozogamicin for Injection) Myozyme (Alglucosidasealfa) Nafcillin Injection (Nafcillin Sodium) Nafcillin Sodium (NafcillinInjection) Naltrexone XR Inj (Vivitrol) Naprosyn (naproxen) NeoProfen(Ibuprofen Lysine Injection) Nandrol Decanoate Neostigmine Methylsulfate(Neostigmine Methylsulfate Injection) NEO-GAA NeoTect (Technetium Tc 99mDepreotide Injection) Nephramine (Essential Amino Acid Injection)Neulasta (pegfilgrastim) Neupogen (Filgrastim) Novolin NovologNeoRecormon Neutrexin (Trimetrexate Glucuronate Inj) NPH (N) Nexterone(Amiodarone HCl Injection) Norditropin (Somatropin Injection) NormalSaline (Sodium Chloride Injection) Novantrone (Mitoxantrone forInjection Concentrate) Novolin 70/30 Innolet (70% NPH, Human InsulinIsophane Suspension and 30% Regular, Human Insulin Injection) NovoLog(Insulin Aspart [rDNA origin] Inj) Nplate (romiplostim) Nutropin(Somatropin (rDNA origin) for Inj) Nutropin AQ Nutropin Depot(Somatropin (rDNA origin) for Inj) Octreotide Acetate Injection(Sandostatin LAR) Ocrelizumab Ofatumumab Injection (Arzerra) OlanzapineExtended Release Injectable Suspension (Zyprexa Relprevv) OmnitargOmnitrope (Somatropin [rDNA origin] Injection) Ondansetron HydrochlorideInjection (Zofran Injection) OptiMARK (Gadoversetamide Injection)Optiray Injection (Ioversol Injection) Orencia Osmitrol Injection inAviva (Mannitol Injection in Aviva Plastic Vessel) Osmitrol Injection inViaflex (Mannitol Injection in Viaflex Plastic Vessel) OsteoprotegrinOvidrel (Choriogonadotropin Alfa Injection) Oxacillin (Oxacillin forInjection) Oxaliplatin Injection (Eloxatin) Oxytocin Injection (Pitocin)Paliperidone Palmitate Extended-Release Injectable Suspension (InvegaSustenna) Pamidronate Disodium Injection (Pamidronate DisodiumInjection) Panitumumab Injection for Intravenous Use (Vectibix)Papaverine Hydrochloride Injection (Papaverine Injection) PapaverineInjection (Papaverine Hydrochloride Injection) Parathyroid HormoneParicalcitol Injection Fliptop Vial (Zemplar Injection) PARP InhibitorPediarix PEGIntron Peginterferon Pegfilgrastim Penicillin G Benzathineand Penicillin G Procaine Pentetate Calcium Trisodium Inj (Ca-DTPA)Pentetate Zinc Trisodium Injection (Zn-DTPA) Pepcid Injection(Famotidine Injection) Pergonal Pertuzumab Phentolamine Mesylate(Phentolamine Mesylate for Injection) Physostigmine Salicylate(Physostigmine Salicylate (injection)) Physostigmine Salicylate(injection) (Physostigmine Salicylate) Piperacillin and TazobactamInjection (Zosyn) Pitocin (Oxytocin Injection) Plasma-Lyte 148 (MultipleElectrolytes Inj) Plasma-Lyte 56 and Dextrose (Multiple Electrolytes andDextrose Injection in Viaflex Plastic Vessel) PlasmaLyte PlerixaforInjection (Mozobil) Polidocanol Injection (Asclera) Potassium ChloridePralatrexate Solution for Intravenous Injection (Folotyn) PramlintideAcetate Injection (Symlin) Premarin Injection (Conjugated Estrogens forInjection) Prep kit for Technetium Tc99 Sestamibi for Injection(Cardiolite) Prevacid I.V. (Lansoprazole for Injection) Primaxin I.V.(Imipenem and Cilastatin for Injection) Prochymal Procrit ProgesteroneProHance (Gadoteridol Injection Solution) Prolia (Denosumab Injection)Promethazine HCl Injection (Promethazine Hydrochloride Injection)Propranolol Hydrochloride Injection (Propranolol HydrochlorideInjection) Quinidine Gluconate Injection (Quinidine Injection) QuinidineInjection (Quinidine Gluconate Injection) R-Gene 10 (ArginineHydrochloride Injection) Ranibizumab Injection (Lucentis) RanitidineHydrochloride Injection (Zantac Injection) Raptiva Reclast (ZoledronicAcid Injection) Recombivarix HB Regadenoson Injection (Lexiscan) ReglanInjection (Metoclopramide Injection) Remicade Renagel Renvela (SevelamerCarbonate) Repronex (Menotropins for Injection) Retrovir IV (ZidovudineInjection) rhApo2L/TRAIL Ringer's and 5% Dextrose Injection (Ringers inDextrose) Ringer's Injection (Ringers Injection) Rituxan RituximabRocephin (ceftriaxone) Rocuronium Bromide Injection (Zemuron) Roferon-A(interferon alfa-2a) Romazicon (flumazenil) Romidepsin for Injection(Istodax) Saizen (Somatropin Injection) Sandostatin LAR (OctreotideAcetate Injection) Sclerostin Ab Sensipar (cinacalcet) Sensorcaine(Bupivacaine HCl Injections) Septocaine (Articane HCl and EpinephrineInjection) Serostim LQ (Somatropin (rDNA origin) Injection) SimponiInjection (Golimumab Injection) Sodium Acetate (Sodium AcetateInjection) Sodium Bicarbonate (Sodium Bicarbonate 5% Injection) SodiumLactate (Sodium Lactate Injection in AVIVA) Sodium Phenylacetate andSodium Benzoate Injection (Ammonul) Somatropin (rDNA origin) for Inj(Nutropin) Sporanox Injection (Itraconazole Injection) Stelara Injection(Ustekinumab) Stemgen Sufenta (Sufentanil Citrate Injection) SufentanilCitrate Injection (Sufenta) Sumavel Sumatriptan Injection (Alsuma)Symlin Symlin Pen Systemic Hedgehog Antagonist Synvisc-One (Hylan G-F 20Single Intra-articular Injection) Tarceva Taxotere (Docetaxel forInjection) Technetium Tc 99m Telavancin for Injection (Vibativ)Temsirolimus Injection (Torisel) Tenormin I.V. Injection (Atenolol Inj)Teriparatide (rDNA origin) Injection (Forteo) Testosterone CypionateTestosterone Enanthate Testosterone Propionate Tev-Tropin (Somatropin,rDNA Origin, for Injection) tgAAC94 Thallous Chloride TheophyllineThiotepa (Thiotepa Injection) Thymoglobulin (Anti-Thymocyte Globulin(Rabbit) Thyrogen (Thyrotropin Alfa for Injection) Ticarcillin Disodiumand Clavulanate Potassium Galaxy (Timentin Injection) Tigan Injection(Trimethobenzamide Hydrochloride Injectable) Timentin Injection(Ticarcillin Disodium and Clavulanate Potassium Galaxy) TNKaseTobramycin Injection (Tobramycin Injection) Tocilizumab Injection(Actemra) Torisel (Temsirolimus Injection) Totect (Dexrazoxane forInjection, Intravenous Infusion Only) Trastuzumab-DM1 Travasol (AminoAcids (Injection)) Treanda (Bendamustine Hydrochloride Injection)Trelstar (Triptorelin Pamoate for Injectable Suspension) TriamcinoloneAcetonide Triamcinolone Diacetate Triamcinolone Hexacetonide InjectableSuspension (Aristospan Injection 20 mg) Triesence (TriamcinoloneAcetonide Injectable Suspension) Trimethobenzamide HydrochlorideInjectable (Tigan Injection) Trimetrexate Glucuronate Inj (Neutrexin)Triptorelin Pamoate for Injectable Suspension (Trelstar) TwinjectTrivaris (Triamcinolone Acetonide Injectable Suspension) Trisenox(Arsenic Trioxide Injection) Twinrix Typhoid Vi Ultravist (IopromideInjection) Urofollitropin for Injection (Metrodin) Urokinase Injection(Kinlytic) Ustekinumab (Stelara Injection) Ultralente (U) Valium(diazepam) Valproate Sodium Injection (Depacon) Valtropin (SomatropinInjection) Vancomycin Hydrochloride (Vancomycin Hydrochloride Injection)Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride) Vaprisol(Conivaptan Hcl Injection) VAQTA Vasovist (Gadofosveset TrisodiumInjection for Intravenous Use) Vectibix (Panitumumab Injection forIntravenous Use) Venofer (Iron Sucrose Injection) Verteporfin Inj(Visudyne) Vibativ (Telavancin for Injection) Victoza (Liraglutide[rDNA] Injection) Vimpat (lacosamide Tablet and Injection) VinblastineSulfate (Vinblastine Sulfate Injection) Vincasar PFS (VincristineSulfate Injection) Victoza Vincristine Sulfate (Vincristine SulfateInjection) Visudyne (Verteporfin Inj) Vitamin B-12 Vivitrol (NaltrexoneXR Inj) Voluven (Hydroxyethyl Starch in Sodium Chloride Injection)Xeloda Xenical (orlistat) Xeomin (Incobotulinumtoxin A for Injection)Xolair Zantac Injection (Ranitidine Hydrochloride Injection) ZemplarInjection (Paricalcitol Injection Fliptop Vial) Zemuron (RocuroniumBromide Injection) Zenapax (daclizumab) Zevalin Zidovudine Injection(Retrovir IV) Zithromax Injection (Azithromycin) Zn-DTPA (Pentetate ZincTrisodium Injection) Zofran Injection (Ondansetron HydrochlorideInjection) Zingo Zoledronic Acid for Inj (Zometa) Zoledronic AcidInjection (Reclast) Zometa (Zoledronic Acid for Inj) Zosyn (Piperacillinand Tazobactam Injection) Zyprexa Relprevv (Olanzapine Extended ReleaseInjectable Suspension) Liquid Drugs (Non-Injectable) Ability AccuNeb(Albuterol Sulfate Inhalation Solution) Actidose Aqua (ActivatedCharcoal Suspension) Activated Charcoal Suspension (Actidose Aqua) Advair Agenerase Oral Solution (Amprenavir Oral Solution) Akten (LidocaineHydrochloride Ophthalmic Gel) Alamast (Pemirolast Potassium OphthalmicSolution) Albumin (Human) 5% Solution (Buminate 5%) Albuterol SulfateInhalation Solution Alinia Alocril Alphagan Alrex Alvesco AmprenavirOral Solution Analpram-HC Arformoterol Tartrate Inhalation Solution(Brovana) Aristospan Injection 20 mg (Triamcinolone HexacetonideInjectable Suspension) Asacol Asmanex Astepro Astepro (AzelastineHydrochloride Nasal Spray) Atrovent Nasal Spray (Ipratropium BromideNasal Spray) Atrovent Nasal Spray 0.06 Augmentin ES-600 Azasite(Azithromycin Ophthalmic Solution) Azelaic Acid (Finacea Gel) AzelastineHydrochloride Nasal Spray (Astepro) Azelex (Azelaic Acid Cream) Azopt(Brinzolamide Ophthalmic Suspension) Bacteriostatic Saline Balanced SaltBepotastine Bactroban Nasal Bactroban Beclovent Benzac W BetimolBetoptic S Bepreve Bimatoprost Ophthalmic Solution Bleph 10(Sulfacetamide Sodium Ophthalmic Solution 10%) Brinzolamide OphthalmicSuspension (Azopt) Bromfenac Ophthalmic Solution (Xibrom) BromhistBrovana (Arformoterol Tartrate Inhalation Solution) BudesonideInhalation Suspension (Pulmicort Respules) Gambia (Diclofenac Potassiumfor Oral Solution) Capex Carac Carboxine-PSE Carnitor Cayston (Aztreonamfor Inhalation Solution) Cellcept Centany Cerumenex Ciloxan OphthalmicSolution (Ciprofloxacin HCL Ophthalmic Solution) Ciprodex CiprofloxacinHCL Ophthalmic Solution (Ciloxan Ophthalmic Solution) ClemastineFumarate Syrup (Clemastine Fumarate Syrup) CoLyte (PEG ElectrolytesSolution) Combiven Comtan Condylox Cordran Cortisporin OphthalmicSuspension Cortisporin Otic Suspension Cromolyn Sodium InhalationSolution (Intal Nebulizer Solution) Cromolyn Sodium Ophthalmic Solution(Opticrom) Crystalline Amino Acid Solution with Electrolytes (AminosynElectrolytes) Cutivate Cuvposa (Glycopyrrolate Oral Solution)Cyanocobalamin (CaloMist Nasal Spray) Cyclosporine Oral Solution(Gengraf Oral Solution) Cyclogyl Cysview (HexaminolevulinateHydrochloride Intravesical Solution) DermOtic Oil (FluocinoloneAcetonide Oil Ear Drops) Desmopressin Acetate Nasal Spray DDAVPDerma-Smoothe/FS Dexamethasone Intensol Dianeal Low Calcium Dianeal PDDiclofenac Potassium for Oral Solution (Gambia) Didanosine PediatricPowder for Oral Solution (Videx) Differin Dilantin 125 (Phenytoin OralSuspension) Ditropan Dorzolamide Hydrochloride Ophthalmic Solution(Trusopt) Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution(Cosopt) Dovonex Scalp (Calcipotriene Solution) Doxycycline Calcium OralSuspension (Vibramycin Oral) Efudex Elaprase (Idursulfase Solution)Elestat (Epinastine HCl Ophthalmic Solution) Elocon Epinastine HClOphthalmic Solution (Elestat) Epivir HBV Epogen (Epoetin alfa)Erythromycin Topical Solution 1.5% (Staticin) Ethiodol (Ethiodized Oil)Ethosuximide Oral Solution (Zarontin Oral Solution) E u rax Extraneal(Icodextrin Peritoneal Dialysis Solution) Felbatol Feridex I.V.(Ferumoxides Injectable Solution) Flovent Floxin Otic (Ofloxacin OticSolution) Flo-Pred (Prednisolone Acetate Oral Suspension) FluoroplexFlunisolide Nasal Solution (Flunisolide Nasal Spray 0.025%)Fluorometholone Ophthalmic Suspension (FML) Flurbiprofen SodiumOphthalmic Solution (Ocufen) FML Foradil Formoterol Fumarate InhalationSolution (Perforomist) Fosamax Furadantin (Nitrofurantoin OralSuspension) Furoxone Gammagard Liquid (Immune Globulin Intravenous(Human) 10%) Gantrisin (Acetyl Sulfisoxazole Pediatric Suspension)Gatifloxacin Ophthalmic Solution (Zymar) Gengraf Oral Solution(Cyclosporine Oral Solution) Glycopyrrolate Oral Solution (Cuvposa)Halcinonide Topical Solution (Halog Solution) Halog Solution(Halcinonide Topical Solution) HEP-LOCK U/P (Preservative-Free HeparinLock Flush Solution) Heparin Lock Flush Solution (Hepflush 10)Hexaminolevulinate Hydrochloride Intravesical Solution (Cysview)Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab Elixir)Hydroquinone 3% Topical Solution (Melquin-3 Topical Solution) IAPAntagonist Isopto Ipratropium Bromide Nasal Spray (Atrovent Nasal Spray)Itraconazole Oral Solution (Sporanox Oral Solution) KetorolacTromethamine Ophthalmic Solution (Acular LS) Kaletra Lanoxin LexivaLeuprolide Acetate for Depot Suspension (Lupron Depot 11.25 mg)Levobetaxolol Hydrochloride Ophthalmic Suspension (Betaxon)Levocarnitine Tablets, Oral Solution, Sugar-Free (Carnitor) LevofloxacinOphthalmic Solution 0.5% (Quixin) Lidocaine HCl Sterile Solution(Xylocaine MPF Sterile Solution) Lok Pak (Heparin Lock Flush Solution)Lorazepam Intensol Lortab Elixir (Hydrocodone Bitartrate andAcetaminophen Oral Solution) Lotemax (Loteprednol Etabonate OphthalmicSuspension) Loteprednol Etabonate Ophthalmic Suspension (Alrex) LowCalcium Peritoneal Dialysis Solutions (Dianeal Low Calcium) Lumigan(Bimatoprost Ophthalmic Solution 0.03% for Glaucoma) Lupron Depot 11.25mg (Leuprolide Acetate for Depot Suspension) Megestrol Acetate OralSuspension (Megestrol Acetate Oral Suspension) MEK Inhibitor MepronMesnex Mestinon Mesalamine Rectal Suspension Enema (Rowasa) Melquin-3Topical Solution (Hydroquinone 3% Topical Solution) MetMab MethyldopateHcl (Methyldopate Hydrochloride Injection, Solution) Methylin OralSolution (Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5 mL)Methylprednisolone Acetate Injectable Suspension (Depo Medrol)Methylphenidate HCl Oral Solution 5 mg/5 ml and 10 mg/5 ml (MethylinOral Solution) Methylprednisolone sodium succinate (Solu Medrol)Metipranolol Ophthalmic Solution (Optipranolol) Migranal Miochol-E(Acetylcholine Chloride Intraocular Solution) Micro-K for LiquidSuspension (Potassium Chloride Extended Release Formulation for LiquidSuspension) Minocin (Minocycline Hydrochloride Oral Suspension) NasacortNeomycin and Polymyxin B Sulfates and Hydrocortisone NepafenacOphthalmic Suspension (Nevanac) Nevanac (Nepafenac OphthalmicSuspension) Nitrofurantoin Oral Suspension (Furadantin) Noxafil(Posaconazole Oral Suspension) Nystatin (oral) (Nystatin OralSuspension) Nystatin Oral Suspension (Nystatin (oral)) Ocufen(Flurbiprofen Sodium Ophthalmic Solution) Ofloxacin Ophthalmic Solution(Ofloxacin Ophthalmic Solution) Ofloxacin Otic Solution (Floxin Otic)Olopatadine Hydrochloride Ophthalmic Solution (Pataday) Opticrom(Cromolyn Sodium Ophthalmic Solution) Optipranolol (MetipranololOphthalmic Solution) Patanol Pediapred PerioGard Phenytoin OralSuspension (Dilantin 125) Phisohex Posaconazole Oral Suspension(Noxafil) Potassium Chloride Extended Release Formulation for LiquidSuspension (Micro-K for Liquid Suspension) Pataday (OlopatadineHydrochloride Ophthalmic Solution) Patanase Nasal Spray (OlopatadineHydrochloride Nasal Spray) PEG Electrolytes Solution (CoLyte) PemirolastPotassium Ophthalmic Solution (Alamast) Penlac (Ciclopirox TopicalSolution) PENNSAID (Diclofenac Sodium Topical Solution) Perforomist(Formoterol Fumarate Inhalation Solution) Peritoneal Dialysis SolutionPhenylephrine Hydrochloride Ophthalmic Solution (Neo-Synephrine)Phospholine Iodide (Echothiophate Iodide for Ophthalmic Solution)Podofilox (Podofilox Topical Solution) Pred Forte (Prednisolone AcetateOphthalmic Suspension) Pralatrexate Solution for Intravenous Injection(Folotyn) Pred Mild Prednisone Intensol Prednisolone Acetate OphthalmicSuspension (Pred Forte) Prevacid PrismaSol Solution (SterileHemofiltration Hemodiafiltration Solution) Pro Air Proglycem ProHance(Gadoteridol Injection Solution) Proparacaine Hydrochloride OphthalmicSolution (Alcaine) Propine Pulmicort Pulmozyme Quixin (LevofloxacinOphthalmic Solution 0.5%) QVAR Rapamune Rebetol Relacon-HC Rotarix(Rotavirus Vaccine, Live, Oral Suspension) Rotavirus Vaccine, Live, OralSuspension (Rotarix) Rowasa (Mesalamine Rectal Suspension Enema) Sabril(Vigabatrin Oral Solution) Sacrosidase Oral Solution (Sucraid)Sandimmune Sepra Serevent Diskus Solu Cortef (Hydrocortisone SodiumSuccinate) Solu Medrol (Methylprednisolone sodium succinate) SpirivaSporanox Oral Solution (Itraconazole Oral Solution) Staticin(Erythromycin Topical Solution 1.5%) Stalevo Starlix SterileHemofiltration Hemodiafiltration Solution (PrismaSol Solution) Sti mateSucralfate (Carafate Suspension) Sulfacetamide Sodium OphthalmicSolution 10% (Bleph 10) Synarel Nasal Solution (Nafarelin Acetate NasalSolution for Endometriosis) Taclonex Scalp (Calcipotriene andBetamethasone Dipropionate Topical Suspension) Tamiflu Tobi TobraDexTobradex ST (Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05%)Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05% (Tobradex ST)Timolol Timoptic Travatan Z Treprostinil Inhalation Solution (Tyvaso)Trusopt (Dorzolamide Hydrochloride Ophthalmic Solution) Tyvaso(Treprostinil Inhalation Solution) Ventolin Vfend Vibramycin Oral(Doxycycline Calcium Oral Suspension) Videx (Didanosine Pediatric Powderfor Oral Solution) Vigabatrin Oral Solution (Sabril) Viokase ViraceptViramune Vitamin K1 (Fluid Colloidal Solution of Vitamin K1) VoltarenOphthalmic (Diclofenac Sodium Ophthalmic Solution) Zarontin OralSolution (Ethosuximide Oral Solution) Ziagen Zyvox Zymar (GatifloxacinOphthalmic Solution) Zymaxid (Gatifloxacin Ophthalmic Solution) DrugClasses 5-alpha-reductase inhibitors 5-aminosalicylates 5HT3 receptorantagonists adamantane antivirals adrenal cortical steroids adrenalcorticosteroid inhibitors adrenergic bronchodilators agents forhypertensive emergencies agents for pulmonary hypertension aldosteronereceptor antagonists alkylating agents alpha-adrenoreceptor antagonistsalpha-glucosidase inhibitors alternative medicines amebicidesaminoglycosides aminopenicillins aminosalicylates amylin analogsAnalgesic Combinations Analgesics androgens and anabolic steroidsangiotensin converting enzyme inhibitors angiotensin II inhibitorsanorectal preparations anorexiants antacids anthelminticsanti-angiogenic ophthalmic agents anti-CTLA-4 monoclonal antibodiesanti-infectives antiadrenergic agents, centrally acting antiadrenergicagents, peripherally acting antiandrogens antianginal agentsantiarrhythmic agents antiasthmatic combinationsantibiotics/antineoplastics anticholinergic antiemetics anticholinergicantiparkinson agents anticholinergic bronchodilators anticholinergicchronotropic agents anticholinergics/antispasmodics anticoagulantsanticonvulsants antidepressants antidiabetic agents antidiabeticcombinations antidiarrheals antidiuretic hormones antidotesantiemetic/antivertigo agents antifungals antigonadotropic agentsantigout agents antihistamines antihyperlipidemic agentsantihyperlipidemic combinations anti hypertensive combinationsantihyperuricemic agents antimalarial agents antimalarial combinationsantimalarial quinolines anti metabolites antimigraine agentsantineoplastic detoxifying agents antineoplastic interferonsantineoplastic monoclonal antibodies antineoplastics antiparkinsonagents antiplatelet agents antipseudomonal penicillins antipsoriaticsantipsychotics antirheumatics antiseptic and germicides antithyroidagents antitoxins and antivenins antituberculosis agentsantituberculosis combinations antitussives antiviral agents antiviralcombinations antiviral interferons anxiolytics, sedatives, and hypnoticsaromatase inhibitors atypical antipsychotics azole antifungals bacterialvaccines barbiturate anticonvulsants barbiturates BCR-ABL tyrosinekinase inhibitors benzodiazepine anticonvulsants benzodiazepinesbeta-adrenergic blocking agents beta-lactamase inhibitors bile acidsequestrants biologicals bisphosphonates bone resorption inhibitorsbronchodilator combinations bronchodilators calcitonin calcium channelblocking agents carbamate anticonvulsants carbapenems carbonic anhydraseinhibitor anticonvulsants carbonic anhydrase inhibitors cardiacstressing agents cardioselective beta blockers cardiovascular agentscatecholamines CD20 monoclonal antibodies CD33 monoclonal antibodiesCD52 monoclonal antibodies central nervous system agents cephalosporinscerumenolytics chelating agents chemokine receptor antagonist chloridechannel activators cholesterol absorption inhibitors cholinergicagonists cholinergic muscle stimulants cholinesterase inhibitors CNSstimulants coagulation modifiers colony stimulating factorscontraceptives corticotropin coumarins and indandiones cox-2 inhibitorsdecongestants dermatological agents diagnostic radiopharmaceuticalsdibenzazepine anticonvulsants digestive enzymes dipeptidyl peptidase 4inhibitors diuretics dopaminergic antiparkinsonism agents drugs used inalcohol dependence echinocandins EGFR inhibitors estrogen receptorantagonists estrogens expectorants factor Xa inhibitors fatty acidderivative anticonvulsants fibric acid derivatives first generationcephalosporins fourth generation cephalosporins functional boweldisorder agents gallstone solubilizing agents gamma-aminobutyric acidanalogs gamma-aminobutyric acid reuptake inhibitors gamma-aminobutyricacid transaminase inhibitors gastrointestinal agents general anestheticsgenitourinary tract agents GI stimulants glucocorticoids glucoseelevating agents glycopeptide antibiotics glycoprotein plateletinhibitors glycylcyclines gonadotropin releasing hormonesgonadotropin-releasing hormone antagonists gonadotropins group Iantiarrhythmics group II antiarrhythmics group III antiarrhythmics groupIV antiarrhythmics group V antiarrhythmics growth hormone receptorblockers growth hormones H. pylori eradication agents H2 antagonistshematopoietic stem cell mobilizer heparin antagonists heparins HER2inhibitors herbal products histone deacetylase inhibitors hormonereplacement therapy hormones hormones/antineoplastics hydantoinanticonvulsants illicit (street) drugs immune globulins immunologicagents immunosuppressive agents impotence agents in vivo diagnosticbiologicals incretin mimetics inhaled anti-infectives inhaledcorticosteroids inotropic agents insulin insulin-like growth factorintegrase strand transfer inhibitor interferons intravenous nutritionalproducts iodinated contrast media ionic iodinated contrast media ironproducts ketolides laxatives leprostatics leukotriene modifierslincomycin derivatives lipoglycopeptides local injectable anestheticsloop diuretics lung surfactants lymphatic staining agents lysosomalenzymes macrolide derivatives macrolides magnetic resonance imagingcontrast media mast cell stabilizers medical gas meglitinides metabolicagents methylxanthines mineralocorticoids minerals and electrolytesmiscellaneous agents miscellaneous analgesics miscellaneous antibioticsmiscellaneous anticonvulsants miscellaneous antidepressantsmiscellaneous antidiabetic agents miscellaneous antiemeticsmiscellaneous antifungals miscellaneous antihyperlipidemic agentsmiscellaneous antimalarials miscellaneous antineoplastics miscellaneousantiparkinson agents miscellaneous antipsychotic agents miscellaneousantituberculosis agents miscellaneous antivirals miscellaneousanxiolytics, sedatives and hypnotics miscellaneous biologicalsmiscellaneous bone resorption inhibitors miscellaneous cardiovascularagents miscellaneous central nervous system agents miscellaneouscoagulation modifiers miscellaneous diuretics miscellaneousgenitourinary tract agents miscellaneous Cl agents miscellaneoushormones miscellaneous metabolic agents miscellaneous ophthalmic agentsmiscellaneous otic agents miscellaneous respiratory agents miscellaneoussex hormones miscellaneous topical agents miscellaneous uncategorizedagents miscellaneous vaginal agents mitotic inhibitors monoamine oxidaseinhibitors monoclonal antibodies mouth and throat products mTORinhibitors mTOR kinase inhibitors mucolytics multikinase inhibitorsmuscle relaxants mydriatics narcotic analgesic combinations narcoticanalgesics nasal anti-infectives nasal antihistamines and decongestantsnasal lubricants and irrigations nasal preparations nasal steroidsnatural penicillins neuraminidase inhibitors neuromuscular blockingagents next generation cephalosporins nicotinic acid derivativesnitrates NNRTIs non-cardioselective beta blockers non-iodinated contrastmedia non-ionic iodinated contrast media non-sulfonylureas nonsteroidalanti-inflammatory agents norepinephrine reuptake inhibitorsnorepinephrine-dopamine reuptake inhibitors nucleoside reversetranscriptase inhibitors (NRTIs) nutraceutical products nutritionalproducts ophthalmic anesthetics ophthalmic anti-infectives ophthalmicanti-inflammatory agents ophthalmic antihistamines and decongestantsophthalmic diagnostic agents ophthalmic glaucoma agents ophthalmiclubricants and irrigations ophthalmic preparations ophthalmic steroidsophthalmic steroids with anti-infectives ophthalmic surgical agents oralnutritional supplements otic anesthetics otic anti-infectives oticpreparations otic steroids otic steroids with anti-infectivesoxazolidinedione anticonvulsants parathyroid hormone and analogspenicillinase resistant penicillins penicillins peripheral opioidreceptor antagonists peripheral vasodilators peripherally actingantiobesity agents phenothiazine antiemetics phenothiazineantipsychotics phenylpiperazine antidepressants plasma expandersplatelet aggregation inhibitors platelet-stimulating agents polyenespotassium-sparing diuretics probiotics progesterone receptor modulatorsprogestins prolactin inhibitors prostaglandin D2 antagonists proteaseinhibitors proton pump inhibitors psoralens psychotherapeutic agentspsychotherapeutic combinations purine nucleosides pyrrolidineanticonvulsants quinolones radiocontrast agents radiologic adjunctsradiologic agents radiologic conjugating agents radiopharmaceuticalsRANK ligand inhibitors recombinant human erythropoietins renininhibitors respiratory agents respiratory inhalant products rifamycinderivatives salicylates sclerosing agents second generationcephalosporins selective estrogen receptor modulators selectiveserotonin reuptake inhibitors serotonin-norepinephrine reuptakeinhibitors serotoninergic neuroenteric modulators sex hormonecombinations sex hormones skeletal muscle relaxant combinations skeletalmuscle relaxants smoking cessation agents somatostatin and somatostatinanalogs spermicides statins sterile irrigating solutions streptomycesderivatives succinimide anticonvulsants sulfonamides sulfonylureassynthetic ovulation stimulants tetracyclic antidepressants tetracyclinestherapeutic radiopharmaceuticals thiazide diuretics thiazolidinedionesthioxanthenes third generation cephalosporins thrombin inhibitorsthrombolytics thyroid drugs tocolytic agents topical acne agents topicalagents topical anesthetics topical anti-infectives topical antibioticstopical antifungals topical antihistamines topical antipsoriaticstopical antivirals topical astringents topical debriding agents topicaldepigmenting agents topical emollients topical keratolytics topicalsteroids topical steroids with anti-infectives toxoids triazineanticonvulsants tricyclic antidepressants trifunctional monoclonalantibodies tumor necrosis factor (TNF) inhibitors tyrosine kinaseinhibitors ultrasound contrast media upper respiratory combinations ureaanticonvulsants urinary anti-infectives urinary antispasmodics urinarypH modifiers uterotonic agents vaccine vaccine combinations vaginalanti-infectives vaginal preparations vasodilators vasopressinantagonists vasopressors VEGF/VEGFR inhibitors viral vaccinesviscosupplementation agents vitamin and mineral combinations vitaminsDiagnostic Tests 1 7-Hydroxyprogesterone ACE (Angiotensin I convertingenzyme) Acetaminophen Acid phosphatase ACTH Activated clotting timeActivated protein C resistance Adrenocorticotropic hormone (ACTH)Alanine aminotransferase (ALT) Albumin Aldolase Aldosterone Alkalinephosphatase Alkaline phosphatase (ALP) Alpha-antitrypsinAlpha-fetoprotein Alpha-fetoprotien Ammonia levels Amylase ANA(antinuclear antibodies) ANA (antinuclear antibodies)Angiotensin-converting enzyme (ACE) Anion gap Anticardiolipin antibodyAnticardiolipin antibodies (ACA) Anti-centromere antibody Antidiuretichormone Anti-DNA Anti-Dnase-B Anti-Gliadin antibody Anti-glomerularbasement membrane antibody Anti-HBc (Hepatitis B core antibodiesAnti-HBs (Hepatitis B surface antibody Antiphospholipid antibodyAnti-RNA polymerase Anti-Smith (Sm) antibodies Anti-Smooth Muscleantibody Antistreptolysin 0 (ASO) Antithrombin III Anti-Xa activityAnti-Xa assay Apolipoproteins Arsenic Aspartate aminotransferase (AST)B12 Basophil Beta-2-Microglobulin Beta-hydroxybutyrate B-HCG BilirubinBilirubin, direct Bilirubin, indirect Bilirubin, total Bleeding timeBlood gases (arterial) Blood urea nitrogen (BUN) BUN BUN (blood ureanitrogen) CA 125 CA 15-3 Calcitonin Calcium Calcium (ionized) Carbonmonoxide (CO) Carcinoembryonic antigen (CEA) CBC CEA (carcinoembryonicantigen) Ceruloplasmin CH50Chloride Cholesterol Cholesterol, HDL Clotlysis time Clot retraction time CMP C02 Cold agglutinins Complement C3Copper Corticotrophin releasing hormone (CRH) stimulation test CortisolCortrosyn stimulation test C-peptide CPK (Total) CPK-MB C-reactiveprotein Creatinine Creatinine kinase (CK) Cryoglobulins DAT (Directantiglobulin test) D-Dimer Dexamethasone suppression test DHEA-S DiluteRussell viper venom Elliptocytes Eosinophil Erythrocyte sedimentationrate (ESR) Estradiol Estriol Ethanol Ethylene glycol Euglobulin lysisFactor V Leiden Factor VIII inhibitor Factor VIII level Ferritin Fibrinsplit products Fibrinogen Folate Folate (serum Fractional excretion ofsodium (FENA) FSH (follicle stimulating factor) FTA-ABS Gamma glutamyltransferase (GOT) Gastrin GGTP (Gamma glutamyl transferase) GlucoseGrowth hormone Haptoglobin HBeAg (Hepatitis Be antigen) HBs-Ag(Hepatitis B surface antigen) Helicobacter pylori Hematocrit Hematocrit(HCT) Hemoglobin Hemoglobin Al C Hemoglobin electrophoresis Hepatitis Aantibodies Hepatitis C antibodies IAT (Indirect antiglobulin test)Immunofixation (IFE) Iron Lactate dehydrogenase (LDH) Lactic acid(lactate) LDH LH (Leutinizing hormone Lipase Lupus anticoagulantLymphocyte Magnesium MCH (mean corpuscular hemoglobin MCHC (meancorpuscular hemoglobin concentration) MCV (mean corpuscular volume)Methylmalonate Monocyte MPV (mean platelet volume) Myoglobin NeutrophilParathyroid hormone (PTH) Phosphorus Platelets (pit) PotassiumPrealbumin Prolactin Prostate specific antigen (PSA) Protein C Protein SPSA (prostate specific antigen) PT (Prothrombin time) PIT (Partialthromboplastin time) RDW (red cell distribution width) Renin RenninReticulocyte count reticulocytes Rheumatoid factor (RF) Sed Rate Serumglutamic-pyruvic transaminase (SGPT Serum protein electrophoresis (SPEP)Sodium T3-resin uptake (T3RU) T4, Free Thrombin time Thyroid stimulatinghormone (TSH) Thyroxine (T4) Total iron binding capacity (TIBC) Totalprotein Transferrin Transferrin saturation Triglyceride (TG) TroponinUric acid Vitamin B12 White blood cells (WBC) Widal test.
 11. The vesselof claim 1, having a minimum shelf life, after the vessel is assembled,of at least two years.
 12. The vessel of claim 11, having a shelf lifeof up to ten years.
 13. The vessel of claim 12, in which the shelf lifeis determined at 20° C.